Benzofurylpyrone derivatives

ABSTRACT

There is provided benzofuryl-α-pyrone derivative represented by the following structural formula (I):  
                 
 
     wherein R 1  represents a hydrogen atom or an alkyl group of 1 to 5 carbons;  
     R 2  represents hydrogen, —CO—R 5  or —SO 2 R 6 ;  
     R 3  represents hydrogen, an alkyl group of 1 to 5 carbons, etc.; and  
     R 4  is a substituent attached to the 4-carbon, 5-carbon, 6-carbon or 7 carbon of the benzofuran ring; and their salts. The compounds are useful as therapeutic agent for hypertriglyceridemia, lipid metabolism enhancers, or prophylactic and/or therapeutic agents for arteriosclerosis.

TECHNICAL FIELD

[0001] The present invention relates to novel benzofuryl-α-pyronederivatives and to medicines containing them as active ingredients. Morespecifically, the invention relates to novel benzofuryl-α-pyronederivatives and to lipid metabolism enhancers, arteriosclerosisprophylactic agents, arteriosclerosis treatment agents, triglyceridebiosynthesis inhibitors, blood triglyceride lowering agents or blood HDLelevating agents containing them as active ingredients.

BACKGROUND ART

[0002] Blood cholesterol and triglycerides (TG) themselves are generallyinsoluble in blood, and they exist as lipoproteins by binding withapolipoproteins. In the body, triglycerides are biosynthesized primarilyin the liver from acetyl CoA as the starting substance which is producedfrom sugars, etc., by 6 different enzymes and one enzyme group (acetylCoA carboxylase, the fatty acid synthase group, fatty acyl CoA synthase,glycerophosphoric acid acyl transferase, lysophosphatidic acid acyltransferase, phosphatidic acid phosphatase and diacylglycerol acyltransferase), and are secreted from the liver into the blood aslipoproteins.

[0003] The condition of a higher-than-normal cholesterol and/ortriglyceride blood level is known as hyperlipidemia. The conditiontermed hyperlipidemia is classified into 6 types based on thelipoproteins in the blood, according to the Fredrickson classification(WHO classification). Types I, IV and V are characterized by increasedtriglycerides only, type IIa by increased cholesterol, and types IIb andIII by increases in both (“Sogo Rinsho”, 43, 871(1994)). This means thatpresent hyperlipidemia drugs (that lower only cholesterol or that lowerboth cholesterol and triglycerides) cannot always be appropriatelyapplied for all hyperlipidemia cases. In particular, type IV accountsfor 40 to 50% of male hyperlipidemia patients (“Rinsho to Kenkyu”, 69,318 (1992)). Most secondary onset forms accompanying diabetes are alsotype IV (“Sogo Rinsho”, 43, 878(1994)).

[0004] Hypertriglyceridemia is a condition in which blood triglyceridelevels are increased, and in the past few years it has been receivingattention among clinical physicians and pharmaceutical manufacturers asa risk factor in arteriosclerosis and ischemic diseases.

[0005] Because most attention in the field of hyperlipidemia, whichincludes hypertriglyceridemia, has been focused on cholesterol alone,which is directly implicated in arteriosclerosis, few drugs have beendeveloped with the aim of lowering triglycerides, and treatment ofhypertriglyceridemia has been limited to the use of clofibrate-basedhypolipidemic drugs or nicotinic acid preparations as the existinghypolipidemic drugs. Because these must be used in high doses and manyaction sites have been reported, there are concerns about a number ofrelated side-effects (The Lipid, 5, 65 to 72 (1994)). It would thereforebe highly desirable to find a new type of drug that has atriglyceride-lowering effect at low doses, exhibits few side-effects andhas a clear action mechanism.

[0006] Hypertriglyceridemia occurs as a result of various causes,including genetic background and, as mentioned above, secondary onsetaccompanying diabetes, etc. (“Sogo Rinsho”, 43, 878(1994)); morespecifically, it is attributed to:

[0007] A. accelerated triglyceride synthesis (secretion) in the liver,and

[0008] B. delayed decomposition of synthesized triglycerides (present inthe blood as lipoproteins) by lipoprotein lipase (LPL) (“Rinsho toKenkyu”, 69, 340(1992)). In particular, for hypertriglyceridemiaaccompanying diabetes, A. is said to be the cause ofnon-insulin-dependent diabetes mellitus (NIDDM), while B. is said to bethe cause of insulin-dependent diabetes mellitus (IDDM) (“Rinsho toKenkyu”, 69, 379(1992)). Consequently, the action mechanism oftherapeutic agents for hypertriglyceridemia is believed to be inhibitionof triglyceride synthesis (secretion) in the liver and/or accelerateddecomposition of synthesized triglycerides (present in the blood aslipoproteins) by lipoprotein lipase (LPL).

[0009] In the prior art there have been known α-pyrone derivatives withsubstitution of a heteroaromatic ring at the C-6 position, for example,in WO 9635664, WO 9514013, WO 9514014, EP 588137, U.S. 4,668,803, FR2665445, Japanese Unexamined Patent Publication SHO No. 49-5976,Japanese Unexamined Patent Publication No. 8-503216, Japanese UnexaminedPatent Publication No. 9-505291, Japanese Unexamined Patent PublicationNo. 9-505293, Japanese Unexamined Patent Publication No. 9-505294,Japanese Unexamined Patent Publication No. 9-505295, or for example, inTetrahedron Letters, 37, 6461 (1996), J. Chem. Research (S), 86 (1994),Chem. Pharm. Bull., 32, 1665 (1984), Chem. Ber., 100, 658 (1967) and J.Org. Chem., 54, 3985 (1989).

[0010] However, no explanation or suggestion has been publishedregarding a triglyceride biosynthesis inhibiting effect, bloodtriglyceride lowering effect or blood HDL elevating effect for any ofthese α-pyrone derivatives of the prior art.

[0011] Of the prior art publications, WO 9635664 and EP 588137 describecompounds with a structural feature wherein phenyl is a substituent atthe C-3 position of the α-pyrone ring, but no description or suggestionis given regarding the use of an alkyl group instead of a phenyl groupas the substituent at the C-3 position of the α-pyrone ring.

[0012] Similarly, U.S. Pat. No. 4,668,803 among the prior artpublications describes α-pyrone derivatives wherein the substituent atthe C-3 position is an acyl group of 2 to 11 carbons or a phenyl group,but no description or suggestion is given regarding the use of an alkylgroup instead of an acyl group of 2 to 11 carbons or a phenyl group asthe substituent at the C-3 position of the α-pyrone ring.

[0013] Also, FR 2665445 among the prior art publications describesα-pyrone derivatives with —S(O)_(n)—R¹ as a substituent at the C-4position, wherein n is 1 or 2 and R¹ represents an alkyl group of 1 to 6carbons, a benzyl group or a phenyl group. However, no description orsuggestion is given regarding the use of OH, OCOR or OSO₂R instead of—S(O)_(n)—R¹ as the substituent at the C-4 position of the α-pyronering.

[0014] Likewise, Japanese Unexamined Patent Publication No. 49-5976among the prior art publications describes α-pyrone derivatives withhydrogen, a lower alkyl group or phenyl as a substituent at the C-4position, but no description or suggestion is given regarding the use ofOH, OCOR or OSO₂R instead of hydrogen, a lower alkyl group or phenyl asthe substituent at the C-4 position of the α-pyrone ring.

[0015] Likewise, Chem. Ber., 100, 658 (1967) among the prior artpublications describes α-pyrone derivatives with hydrogen, methyl orethyl as a substituent at the C-4 position, but no description orsuggestion is given regarding the use of OH, OCOR or OSO₂R instead ofhydrogen, methyl or ethyl as the substituent at the C-4 position of theα-pyrone ring.

[0016] Likewise, J. Chem. Research (S), 86(1994) among the prior artpublications describes α-pyrone derivatives with an SMe group as asubstituent at the C-4 position, but no description or suggestion isgiven regarding the use of OH, OCOR or OSO₂R instead of an SMe group asthe substituent at the C-4 position of the α-pyrone ring.

[0017] In addition, Tetrahedron Letters, 37, 6461 (1996), Chem. Pharm.Bull., 32, 1665 (1984) and J. Org. Chem., 54, 3985 (1989) among theprior art publications describe α-pyrone derivatives with a pyridylgroup substituent at the C-6 position, but no description or suggestionis given regarding the use of a benzofuryl group instead of a pyridylgroup as the substituent at the C-6 position of the α-pyrone ring.

DISCLOSURE OF THE INVENTION

[0018] It is an object of the present invention to providebenzofuryl-α-pyrone derivatives, and especially novelbenzofuryl-α-pyrone derivatives having a benzofuryl group as asubstituent at the C-6 position of the α-pyrone ring.

[0019] It is another object of the invention to provide lipid metabolismenhancers, arteriosclerosis prophylactic agents or arteriosclerosistreatment agents, and especially to provide triglyceride biosynthesisinhibitors, blood triglyceride lowering agents or blood HDL elevatingagents, that contain as active ingredients the novel benzofuryl-α-pyronederivatives having a benzofuryl group as a substituent at the C-6position of the α-pyrone ring.

[0020] The present inventors have conducted much research in light ofthe prior art cited above, and as a result the inventors have found thatbenzofuryl-α-pyrone derivatives, and especially benzofuryl-α-pyronederivatives having a benzofuryl group as a substituent at the C-6position of the α-pyrone ring, have a triglyceride biosynthesisinhibiting effect, a blood triglyceride lowering effect and a blood HDLelevating effect; the present invention have been achieved after stillfurther research on the same.

[0021] Specifically, the present invention provides benzofuryl-α-pyronederivatives (and salts thereof) represented by the following structuralformula (I)

[0022] wherein R¹ represents hydrogen or an alkyl group of 1 to 5carbons;

[0023] R² represents hydrogen, —CO—R⁵ (wherein R⁵ represents hydrogen,an alkyl group of 1 to 5 carbons with optional substituents, acycloalkyl group of 3 to 7 carbons, an aryl group of 6 to 10 carbons ora heterocycle), or —SO₂R⁶ (wherein R⁶ represents an optionallyhalogen-substituted alkyl group of 1 to 5 carbons or aryl group of 6 to10 carbons);

[0024] R³ represents hydrogen, an alkyl group of 1 to 5 carbons, analkenyl group of 2 to 5 carbons, an alkynyl group of 2 to 5 carbons, acycloalkyl group of 3 to 7 carbons, a cycloalkyl group of 3 to 7carbons-alkyl group of 1 to 5 carbons, an aryl group of 6 to 10 carbons,an aralkyl group of 7 to 20 carbons, an alkoxy group of 1 to 5 carbonsor an aryloxy group of 6 to 10 carbons;

[0025] R⁴ is a substituent at the C-4 position, C-5 position, C-6position or C-7 position of the benzofuran ring and represents:

[0026] R^(4a) which represents hydrogen, a nitro group, a cyano group, ahalogen atom, a heterocycle, an alkenyl group of 2 to 5 carbons, analkynyl group of 2 to 5 carbons, an aryl group of 6 to 10 carbons,A=CH(CH₂)_(n)— (wherein A represents an alicyclic heterocycle, “═”represents a double bond and n represents 0, 1 or 2), A=CH(CH₂)_(m)O—(wherein A represents an alicyclic heterocycle, “═” represents a doublebond and m represents 1, 2 or 3), A-SO₂—(CH₂)_(m)— (wherein A representsan alicyclic heterocycle and m represents 1, 2 or 3), —OR⁷ (wherein R⁷represents hydrogen, a cycloalkyl group of 3 to 7 carbons, an aryl groupof 6 to 10 carbons, a heterocycle, an optionally halogen-substitutedalkylsulfonyl group of 1 to 4 carbons, or an arylsulfonyl group of 6 to10 carbons), —O—CO—R⁸ (wherein R⁸ represents hydrogen, an alkyl group of1 to 4 carbons, an aryl group of 6 to 10 carbons, an aralkyl group of 7to 20 carbons or a heterocycle), —NR⁹R¹⁰ (wherein R⁹ and R¹⁰ eachindependently represents hydrogen, an alkyl group of 1 to 4 carbons, anaralkyl group of 7 to 20 carbons, a phenyl group, a heterocycle,—SO₂—R¹¹ (wherein R¹¹ represents an optionally halogen-substituted alkylgroup of 1 to 12 carbons, a heterocycle-substituted alkyl group of 1 to6 carbons, an aryl group of 6 to 10 carbons, a heterocycle or an aralkylgroup of 7 to 20 carbons) or —CO—R¹² (wherein R¹² represents hydrogen,an alkyl group of 1 to 12 carbons, an aryl group of 6 to 10 carbons, anaralkyl group of 7 to 20 carbons, a heterocycle, an alkoxy group of 1 to10 carbons, a heterocycle-substituted alkyl group of 1 to 6 carbons, anaryloxy group of 6 to 10 carbons, a heteroaryloxy group or an aralkyloxygroup of 7 to 20 carbons)), —CO—R¹³ (wherein R¹³ represents hydrogen,—OH, an alkyl group of 1 to 4 carbons, an aryl group of 6 to 10 carbons,a heterocycle, an alkoxy group of 1 to 4 carbons, an aryloxy group of 6to 10 carbons or an aralkyloxy group of 7 to 20 carbons), or —CO—NR¹⁴R¹⁵(wherein R¹⁴ and R¹⁵ each independently represents hydrogen, an alkylgroup of 1 to 4 carbons, a cycloalkyl group of 3 to 7 carbons, an arylgroup of 6 to 10 carbons, an aralkyl group of 7 to 20 carbons, aheterocycle or a heterocycle-substituted alkyl group of 1 to 4 carbons);

[0027] R^(4b) which represents a saturated or unsaturated alkoxy groupof 1 to 6 carbons optionally substituted with 1 to 3 groups selectedfrom the group consisting of halogens, cycloalkyl groups of 3 to 7carbons, phenyl, naphthyl, heterocycles, —OR¹⁶ (wherein R¹⁶ representshydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthylgroup, a benzyl group or a heterocycle), —O—CO—R¹⁶ (wherein R¹⁶represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, anaphthyl group, a benzyl group or a heterocycle), —NR¹⁷R¹⁸ (wherein R¹⁷and R¹⁸ each independently represents hydrogen, an alkyl group of 1 to 4carbons, a heterocycle, an alkylsulfonyl group of 1 to 4 carbons, aphenylsulfonyl group, —SO₂-Het (wherein Het represents a heterocycle),an aminosulfonyl group, a methylaminosulfonyl group, adimethylaminosulfonyl group, a diethylaminosulfonyl group, or an alkylgroup of 1 to 4 carbons substituted with 1 or 2 groups selected fromamong phenyl, heterocycles, phenoxy, —O-Het (wherein Het represents aheterocycle) and hydroxyl, —NH—CO—R¹⁹ (wherein R¹⁹ represents hydrogen,an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, abenzyl group, a heterocycle, an alkoxy group of 1 to 4 carbons or abenzyloxy group), —CO—R²⁰ (wherein R²⁰ represents hydrogen, aheterocycle, an alkoxy group of 1 to 4 carbons, a phenoxy group, abenzyloxy group or —OR²¹ (wherein R²¹ represents hydrogen or aheterocycle)), and —CO—NR²²R²³ (wherein R²² and R²³ each independentlyrepresents hydrogen, an alkyl group of 1 to 4 carbons, a benzyl group ora heterocycle); or

[0028] R^(4C) which represents an alkyl group of 1 to 4 carbonsoptionally substituted with 1 to 3 groups selected from the groupconsisting of halogens, cycloalkyl groups of 3 to 7 carbons, phenyl,naphthyl, heterocycles, —SH, —OR¹⁶ (wherein R¹⁶ represents hydrogen, analkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, abenzyl group or a heterocycle), —O—CO—R¹⁶ (wherein R¹⁶ representshydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthylgroup, a benzyl group or a heterocycle), —NR¹⁷R¹⁸ (wherein R¹⁷ and R¹⁸each independently represents hydrogen, an alkyl group of 1 to 4carbons, a heterocycle, an alkylsulfonyl group of 1 to 4 carbons, aphenylsulfonyl group, —SO₂-Het (wherein Het represents a heterocycle),an aminosulfonyl group, a methylaminosulfonyl group, adimethylaminosulfonyl group, a diethylaminosulfonyl group, or an alkylgroup of 1 to 4 carbons substituted with 1 or 2 groups selected fromamong phenyl, heterocycles, phenoxy, —O-Het (wherein Het represents aheterocycle) and hydroxyl, —NH—CO—R¹⁹ (wherein R¹⁹ represents hydrogen,an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, abenzyl group, a heterocycle, an alkoxy group of 1 to 4 carbons or abenzyloxy group), —CO—R²⁰ (wherein R²⁰ represents hydrogen, aheterocycle, an alkoxy group of 1 to 4 carbons, a phenoxy group, abenzyloxy group or —OR²¹ (wherein R²¹ represents hydrogen or aheterocycle)) and —CO—NR²²R²³ (wherein R²² and R²³ each independentlyrepresents hydrogen, an alkyl group of 1 to 4 carbons, a benzyl group ora heterocycle); and

[0029] the numbers in italics represents the positions on the benzofuranring.

[0030] The present invention further provides pharmaceuticalcompositions comprising a therapeutically effective dose of thebenzofuryl-α-pyrone derivatives represented by structural formula (I)above or their salts, with pharmaceutically acceptable carriers.

[0031] The invention still further provides lipid metabolism enhancers,triglyceride biosynthesis inhibitors, blood triglyceride loweringagents, blood HDL elevating agents, arteriosclerosis prophylactic agentsand arteriosclerosis treatment agents containing as active ingredientsthe benzofuryl-α-pyrone derivatives represented by structural formula(I) above or their salts.

EMBODIMENT FOR CARRYING OUT THE INVENTION

[0032] The terms used alone or in conjunction with other termsthroughout the present specification will now be explained. However, theinvention is in no way restricted by the specific examples listed below.

[0033] “Alkyl” means a linear or branched alkyl group such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,n-pentyl, isopentyl or 3-pentyl.

[0034] “Alkenyl” means a linear or branched alkenyl group such as vinyl,1-propenyl, aryl, isopropenyl, 2-butenyl, 3-butenyl, 1-pentenyl or2-pentenyl.

[0035] “Alkynyl” means a linear or branched alkynyl group such asethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,2-methyl-3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl or 4-pentynyl.

[0036] “Cycloalkyl” means a cycloalkyl group of 3 to 7 carbons such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0037] A “cycloalkyl group of 3 to 7 carbons-alkyl group of 1 to 5carbons” is a group comprising the aforementioned cycloalkyl group of 3to 7 carbons and alkyl group of 1 to 5 carbons, and for example, theremay be mentioned cyclopropylmethyl, cyclopentylmethyl, cyclopentylethyl,cyclohexylmethyl, cyclohexylethyl and cycloheptylmethyl.

[0038] “Aryl” means an aromatic ring of 6 to 10 carbons such as phenylor naphthyl.

[0039] A “heterocycle” is a heterocycle containing as constituents ofthe ring 1 to 4 hetero atoms selected from the group consisting ofoxygen, nitrogen and sulfur, and it may be a 5- or 6-memberedheteroaromatic group such as imidazolyl, thiazolyl, isothiazolyl,pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, oxazolyl orisoxazolyl, or a 5- to 7-membered heteroalicyclic group such asthiazolidinyl, oxazolidinyl, imidazolidinyl, pyrrolidinyl, piperidyl,morpholinyl, piperazinyl, homopiperazinyl, tetrahydrofuryl,tetrahydropyranyl, dioxolanyl, dioxanyl, oxazinyl, thiazinyl, diazinylor pyrazolidinyl; this also includes bicyclic groups condensed ontobenzene, cycloalkyl groups of 3 to 7 carbons and other heteroaromaticrings or heteroalicyclic rings, the heteroaromatic ring orheteroalicyclic ring may also be optionally substituted, and whenchemically possible, the nitrogen atom or sulfur atom may be in anoxidized form.

[0040] “Heteroaryl” means a heteroaromatic group of the heterocyclesdefined above.

[0041] “Aralkyl” represents a group of 7 to 20 carbons comprising theaforementioned alkyl group of 1 to 5 carbons and aryl group of 6 to 10carbons, and for example, there may be mentioned benzyl, phenethyl,phenylpropyl, benzhydryl, trityl and naphthylmethyl.

[0042] “Alkoxy” means a linear or branched alkoxy group such as methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,t-butoxy, n-pentyloxy, isopentyloxy, 3-pentyloxy, 2,2-dimethylpropoxy,n-hexyloxy, 4-methylpentyloxy or 2-ethylbutoxy.

[0043] “Unsaturated alkoxy” means a linear or branched unsaturatedalkoxy group such as vinyloxy, allyloxy, 2-propenyloxy, 2-propynyloxy,2-methyl-2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy,2-butynyloxy, 2-pentenyloxy, 3-hexenyloxy, 5-hexenyloxy or 5-hexynyloxy.

[0044] “Aryloxy” means an aryloxy group of 6 to 10 carbons such asphenoxy or naphthyloxy.

[0045] “Aralkyloxy” represents a group comprising the aforementionedalkoxy group of 1 to 5 carbons and aryl group of 6 to 10 carbons, andfor example, there may be mentioned benzyloxy, phenethyloxy,phenylpropoxy, trityloxy and naphthylmethyloxy.

[0046] “Cycloalkyloxy” means a cycloalkyloxy group of 3 to 7 carbonssuch as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy orcycloheptyloxy.

[0047] “Acyl” means a linear or branched acyl group of 1 to 6 carbonssuch as formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl,trimethylacetyl or 3,3,3-trimethylpropionyl.

[0048] “Arylcarbonyl” means an arylcarbonyl group of 7 to 11 carbonssuch as benzoyl or naphthylcarbonyl.

[0049] “Alkylsulfonyl” means an alkylsulfonyl group of 1 to 5 carbonssuch as methanesulfonyl, ethanesulfonyl or n-propanefulfonyl.

[0050] “Arylsulfonyl” means an arylsulfonyl group of 6 to 10 carbonssuch as phenylsulfonyl or naphthalenesulfonyl.

[0051] The rings of the “aryl”, “phenyl”, “naphthyl” and “heterocycle”may be substituted with 1 to 4 substituents selected from the groupconsisting of, for example, —OH, carboxyl, cyano, phenyl, heterocycles,—SO₂NH₂, —SO₃H, alkylsulfamoyl groups such as methylsulfamoyl,ethylsulfamoyl, dimethylsulfamoyl, etc., phenylsulfamoyl,benzylsulfamoyl, morpholinesulfonyl, alkylsulfonyl groups such asmethanesulfonyl, ethanesulfonyl, n-propanesulfonyl, etc., arylsulfonylgroups such as phenylsulfonyl, naphthalenesulfonyl, etc., amino,methylenedioxy, alkoxy groups of 1 to 5 carbons such as methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentyloxy, etc.,alkylamino groups such as methylamino, dimethylamino, ethylamino,diethylamino, n-propylamino, isopropylamino, n-butylamino,isobutylamino, t-butylamino, etc., acylamino groups such as formamino,acetylamino, propionylamino, n-butyrylamino, etc., alkoxycarbonylaminogroups such as methoxycarbonylamino, ethoxycarbonylamino,n-propoxycarbonylamino, n-butoxycarbonylamino, t-butoxycarbonylamino,etc., aralkyloxycarbonylamino groups such as benzyloxycarbonylamino,naphthylmethyloxycarbonylamino, etc., alkylsulfonylamino groups such asmethanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino, etc.,arylsulfonylamino groups such as phenylsulfonylamino,naphthalenesulfonylamino, etc., nitro, hydroxymethyl, alkyl groups of 1to 5 carbons such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, n-pentyl, etc., aralkyl groups such as benzyl,phenethyl, trityl, naphthylmethyl, etc., aralkyloxy groups such asbenzyloxy, phenethyloxy, phenylpropoxy, trityloxy, naphthylmethyloxy,etc., acyl groups such as formyl, acetyl, propionyl, n-butyryl,isobutyryl, n-valeryl, trimethylacetyl, 3,3,3-trimethylpropionyl, etc.,alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,t-butoxycarbonyl, etc., aryloxycarbonyl groups such as phenoxycarbonyl,naphthyloxycarbonyl, etc., aralkyloxycarbonyl groups such asbenzyloxycarbonyl, phenethyloxycarbonyl, trityloxycarbonyl,naphthylmethyloxycarbonyl, etc., carbamoyl, alkylcarbamoyl groups suchas methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl,n-propylcarbamoyl, n-butylcarbamoyl, etc., halogenated methyl groupssuch as chloromethyl, bromomethyl, trifluoromethyl, etc., and halogenatoms, i.e. fluorine, chlorine, bromine and iodine; when chemicallypossible, these may be substituted with 1 to 3 oxo groups or thiooxogroups.

[0052] In formula (I) above, R¹ represents hydrogen or an alkyl group of1 to 5 carbons. As alkyl groups of 1 to 5 carbons there may bementioned, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl and 3-pentyl.

[0053] As preferred groups for R¹ there may be mentioned hydrogen,methyl, ethyl and isopropyl, and methyl may be mentioned as aparticularly preferred group for R¹.

[0054] In formula (I) above, R² represents hydrogen, —CO—R⁵ (wherein R⁵represents hydrogen, an alkyl group of 1 to 5 carbons with optionalsubstituents, a cycloalkyl group of 3 to 7 carbons, an aryl group of 6to 10 carbons or a heterocycle), or —SO₂R⁶ (wherein R⁶ represents anoptionally halogen-substituted alkyl group of 1 to 5 carbons, or an arylgroup of 6 to 10 carbons).

[0055] When R² is —CO—R⁵ and the R⁵ group is an alkyl group of 1 to 5carbons with an optional substituent, the alkyl group of 1 to 5 carbonsfor R⁵ may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, 3-pentyl, etc., amongwhich methyl, ethyl and isopropyl are preferred.

[0056] Optional substituents of the alkyl group of 1 to 5 carbons for R⁵include all alkyl group substituents known to those skilled in the artand, for example, they include halogen atoms, —OH, carboxyl groups,formyl groups, acyl groups, cyano groups, nitro groups, amino groups,mercapto groups, sulfonate groups, aryl groups of 6 to 10 carbons,heterocycles, cycloalkyl groups of 3 to 7 carbons and their protectedforms; more specifically, there may be mentioned —OH; hydroxyl protectedwith an alkyl group of 1 to 4 carbons, an aryl group of 6 to 10 carbons,an aralkyl group of 7 to 20 carbons, a heterocycle, an acyl group of 1to 5 carbons, an arylcarbonyl group of 7 to 11 carbons or anaralkylcarbonyl group of 8 to 21 carbons; —O—CO-Het (wherein Hetrepresents a heterocycle); cycloalkyl groups of 3 to 7 carbons; arylgroups of 6 to 10 carbons; heterocycles; amino groups; amino groupsprotected with an alkyl group of 1 to 4 carbons, an aralkyl group of 7to 20 carbons, an optionally halogen-substituted alkylsulfonyl group of1 to 4 carbons, an arylsulfonyl group of 6 to 10 carbons, an acyl groupof 1 to 5 carbons, an arylcarbonyl group of 7 to 11 carbons, anaralkylcarbonyl group of 8 to 21 carbons, an alkoxycarbonyl group of 2to 5 carbons, an aralkyloxycarbonyl group of 8 to 21 carbons or aheterocycle; —NH—CO-Het (wherein Het represents a heterocycle); acylgroups of 1 to 5 carbons; carboxyl groups; alkoxycarbonyl groups of 2 to5 carbons; aryloxycarbonyl groups of 7 to 11 carbons; aralkyloxycarbonylgroups of 8 to 21 carbons; —CO—O-Het (wherein Het represents aheterocycle); carbamoyl groups, alkylcarbamoyl groups of 2 to 5 carbons;aralkylcarbamoyl groups of 8 to 21 carbons; —CO—NH-Het (wherein Hetrepresents a heterocycle); and —CO-Het (wherein Het represents aheterocycle). As preferred substituents among these there may bementioned phenyl, aryloxy, amino, t-butoxycarbonylamino,benzyloxycarbonylamino, (benzyloxycarbonylamino)methylamino, acetylaminoand morpholinylcarbonyl.

[0057] When R² is —COR⁵ and the R⁵ group is a cycloalkyl group of 3 to 7carbons, the cycloalkyl group of 3 to 7 carbons for R⁵ may be, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc., among which cyclohexyl is preferred.

[0058] When R² is —COR⁵ and the R⁵ group is an aryl group of 6 to 10carbons, the aryl group of 6 to 10 carbons for R⁵ may be, for example,phenyl, naphthyl, etc., among which phenyl is preferred.

[0059] When R² is —COR⁵ and the R⁵ group is a heterocycle, theheterocycle for R⁵ may be, for example, imidazolyl, thiazolyl,isothiazolyl, pyrazolyl, triazolyl, pyrrolyl, pyridyl, pyrimidinyl,pyrazinyl, furyl, thienyl, isoxazolyl, thiazolidinyl, oxazolidinyl,imidazolidinyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl,tetrahydrofuryl, tetrahydropyranyl, etc., among which pyridyl,pyrrolidinyl and furyl are preferred.

[0060] As preferred groups for R⁵ there may be mentioned alkyl groups of1 to 5 carbons with optional substituents, among which there may bementioned methyl, methyl or ethyl substituted with phenyl, aryloxy,amino, t-butoxycarbonylamino, benzyloxycarbonylamino,(benzyloxycarbonyl)-N-methylamino, acetylamino or morpholinylcarbonyl,and isopropyl; aryl groups of 6 to 10 carbons, among which there may bementioned phenyl; and heterocycles, among which there may be mentionedpyridyl, pyrrolidinyl and furyl.

[0061] When R² is —SO₂R⁶ and the R⁶ group is an optionallyhalogen-substituted alkyl group of 1 to 5 carbons, the optionallyhalogen-substituted alkyl group of 1 to 5 carbons for R⁶ may be, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, chloromethyl, bromomethyl,trifluoromethyl, etc., among which methyl and trifluoromethyl arepreferred.

[0062] When R² is —SO₂R⁶ and R⁶ is an aryl group of 6 to 10 carbons, thearyl group of 6 to 10 carbons for R⁶ may be, for example, phenyl,naphthyl, etc., among which phenyl is preferred.

[0063] As preferred groups for R⁶ there may be mentioned optionallyhalogen-substituted alkyl groups of 1 to 5 carbons, and as particularlypreferred groups for R⁶ there may be mentioned methyl andtrifluoromethyl.

[0064] As preferred groups for R² there may be mentioned hydrogen,—COR⁷⁰ (wherein R⁷⁰ represents an alkyl group of 1 to 5 carbons with anoptional substituent, an aryl group of 6 to 10 carbons or a heterocycle)and optionally halogen-substituted alkylsulfonyl groups of 1 to 5carbons, and as particularly preferred groups for R² there may bementioned hydrogen, —COR⁷¹ (wherein R⁷¹ represents s methyl group; amethyl or ethyl group substituted with phenyl, aryloxy, amino,t-butoxycarbonylamino, benzyloxycarbonylamino,(benzyloxycarbonyl)-N-methylamino, acetylamino or morpholinylcarbonyl;an isopropyl group; a phenyl group; a pyridyl group; a pyrrolidinylgroup; or a furyl group), methanesulfonyl and trifluoromethanesulfonyl.

[0065] In formula (I) above, R³ represents hydrogen, an alkyl group of 1to 5 carbons, an alkenyl group of 2 to 5 carbons, an alkynyl group of 2to 5 carbons, a cycloalkyl group of 3 to 7 carbons, a cycloalkyl of 3 to7 carbons-alkyl group of 1 to 5 carbons, an aryl group of 6 to 10carbons, an aralkyl group of 7 to 20 carbons, an alkoxy group of 1 to 5carbons or an aryloxy group of 6 to 10 carbons.

[0066] When R³ is an alkyl group of 1 to 5 carbons, the alkyl group of 1to 5 carbons may be, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, etc., among whichmethyl, ethyl, isopropyl and n-pentyl are preferred.

[0067] When R³ is an alkenyl group of 2 to 5 carbons, the alkenyl groupof 2 to 5 carbons may be vinyl, allyl, 1-propenyl, isopropenyl,2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, etc., among which2-butenyl is preferred.

[0068] When R³ is an alkynyl group of 2 to 5 carbons, the alkynyl groupof 2 to 5 carbons may be vinyl, allyl, 1-propenyl, isopropenyl,2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, etc., among which2-butenyl is preferred.

[0069] When R³ is a cycloalkyl group of 3 to 7 carbons, the cycloalkylgroup of 3 to 7 carbons may be, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, etc., among which cyclohexyl ispreferred.

[0070] When R³ is a cycloalkyl of 3 to 7 carbons-alkyl group of 1 to 5carbons, the cycloalkyl of 3 to 7 carbons-alkyl group of 1 to 5 carbonsmay be, for example, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, etc., amongwhich cyclopentylmethyl is preferred.

[0071] When R³ is an aryl group of 6 to 10 carbons, the aryl group of 6to 10 carbons may be, for example, phenyl, naphthyl, etc., among whichphenyl is preferred.

[0072] When R³ is an aralkyl group of 7 to 20 carbons, the aralkyl groupof 7 to 20 carbons may be, for example, benzyl, phenethyl, phenylpropyl,benzhydryl, trityl, naphthylmethyl, etc., among which benzyl ispreferred.

[0073] When R³ is an alkoxy group of 1 to 5 carbons, the alkoxy group of1 to 5 carbons may be, for example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, etc., among whichmethoxy is preferred.

[0074] When R³ is an aryloxy group of 6 to 10 carbons, the aryloxy groupof 6 to 10 carbons may be, for example, phenoxy, naphthyloxy, etc.,among which phenoxy is preferred.

[0075] As preferred groups for R³ there may be mentioned alkyl groups of1 to 5 carbons, alkenyl groups of 2 to 5 carbons, cycloalkyl groups of 3to 7 carbons-alkyl groups of 1 to 5 carbons and aralkyl groups of 7 to20 carbons, and as particularly preferred groups for R³ there may bementioned alkyl groups of 1 to 5 carbons, among which methyl, ethyl,isopropyl and n-pentyl are preferred; cycloalkyl groups of 3 to 7carbons-alkyl groups of 1 to 5 carbons, among which cyclopentylmethyl ispreferred; and benzyl.

[0076] In formula (I) above, R⁴ is a substituent at the C-4 position,C-5 position, C-6 position or C-7 position of the benzofuran ring andrepresents:

[0077] R^(4a) which represents hydrogen, a nitro group, a cyano group, ahalogen atom, a heterocycle, an alkenyl group of 2 to 5 carbons, analkynyl group of 2 to 5 carbons, an aryl group of 6 to 10 carbons,A=CH(CH₂)_(n)— (wherein A represents an alicyclic heterocycle, “═”represents a double bond and n represents 0, 1 or 2), A=CH(CH₂)_(m)O—(wherein A represents an alicyclic heterocycle, “═” represents a doublebond and m represents 1, 2 or 3), A-SO₂—(CH₂)_(m)— (wherein A representsan alicyclic heterocycle and m represents 1, 2 or 3), —OR⁷ (wherein R⁷represents hydrogen, a cycloalkyl group of 3 to 7 carbons, an aryl groupof 6 to 10 carbons, a heterocycle or an optionally halogen-substitutedalkylsulfonyl group of 1 to 4 carbons or arylsulfonyl group of 6 to 10carbons), —O—CO—R⁸ (wherein R⁸ represents hydrogen, an alkyl group of 1to 4 carbons, an aryl group of 6 to 10 carbons, an aralkyl group of 7 to20 carbons or a heterocycle), —NR⁹R¹⁰ (wherein R⁹ and R¹⁰ eachindependently represents hydrogen, an alkyl group of 1 to 4 carbons, anaralkyl group of 7 to 20 carbons, a phenyl group, a heterocycle,—SO₂—R¹¹ (wherein R¹¹ represents an optionally halogen-substituted alkylgroup of 1 to 12 carbons, a heterocycle-substituted alkyl group of 1 to6 carbons, an aryl group of 6 to 10 carbons, a heterocycle or an aralkylgroup of 7 to 20 carbons) or —CO—R¹² (wherein R¹² represents hydrogen,an alkyl group of 1 to 12 carbons, an aryl group of 6 to 10 carbons, anaralkyl group of 7 to 20 carbons, a heterocycle, an alkoxy group of 1 to10 carbons, a heterocycle-substituted alkyl group of 1 to 6 carbons, anaryloxy group of 6 to 10 carbons, a heteroaryloxy group or an aralkyloxygroup of 7 to 20 carbons)), —CO—R¹³ (wherein R¹³ represents hydrogen,—OH, an alkyl group of 1 to 4 carbons, an aryl group of 6 to 10 carbons,a heterocycle, an alkoxy group of 1 to 4 carbons, an aryloxy group of 6to 10 carbons or an aralkyloxy group of 7 to 20 carbons) or —CO—NR¹⁴R¹⁵(wherein R¹⁴ and R¹⁵ each independently represents hydrogen, an alkylgroup of 1 to 4 carbons, a cycloalkyl group of 3 to 7 carbons, an arylgroup of 6 to 10 carbons, an aralkyl group of 7 to 20 carbons, aheterocycle or a heterocycle-substituted alkyl group of 1 to 4 carbons);

[0078] R^(4b) which represents a saturated or unsaturated alkoxy groupof 1 to 6 carbons optionally substituted with 1 to 3 groups selectedfrom the group consisting of halogens, cycloalkyl groups of 3 to 7carbons, phenyl, naphthyl, heterocycles, —OR¹⁶ (wherein R¹⁶ representshydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthylgroup, a benzyl group or a heterocycle), —O—CO—R¹⁶ (wherein R¹⁶represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, anaphthyl group, a benzyl group or a heterocycle), —NR¹⁷R¹⁸ (wherein R¹⁷and R¹⁸ each independently represents hydrogen, an alkyl group of 1 to 4carbons, a heterocycle, an alkylsulfonyl group of 1 to 4 carbons, aphenylsulfonyl group, —SO₂-Het (wherein Het represents a heterocycle),an aminosulfonyl group, a methylaminosulfonyl group, adimethylaminosulfonyl group, a diethylaminosulfonyl group, or an alkylgroup of 1 to 4 carbons substituted with 1 or 2 groups selected fromamong phenyl, heterocycles, phenoxy, —O-Het (wherein Het represents aheterocycle) and hydroxyl, —NH—CO—R¹⁹ (wherein R¹⁹ represents hydrogen,an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, abenzyl group, a heterocycle, an alkoxy group of 1 to 4 carbons or abenzyloxy group), —CO—R²⁰ (wherein R²⁰ represents hydrogen, aheterocycle, an alkoxy group of 1 to 4 carbons, a phenoxy group, abenzyloxy group or —OR²¹ (wherein R²¹ represents hydrogen or aheterocycle)) and —CO—NR²²R²³ (wherein R²² and R²³ each independentlyrepresents hydrogen, an alkyl group of 1 to 4 carbons, a benzyl group ora heterocycle); or

[0079] R^(4C) which represents an alkyl group of 1 to 4 carbonsoptionally substituted with 1 to 3 groups selected from the groupconsisting of halogens, cycloalkyl groups of 3 to 7 carbons, phenyl,naphthyl, heterocycles, —SH, —OR¹⁶ (wherein R¹⁶ represents hydrogen, analkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, abenzyl group or a heterocycle), —O—CO—R¹⁶ (wherein R¹⁶ representshydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthylgroup, a benzyl group or a heterocycle), —NR¹⁷R¹⁸ (wherein R¹⁷ and R¹⁸each independently represents hydrogen, an alkyl group of 1 to 4carbons, a heterocycle, an alkylsulfonyl group of 1 to 4 carbons, aphenylsulfonyl group, —SO₂-Het (wherein Het represents a heterocycle),an aminosulfonyl group, a methylaminosulfonyl group, adimethylaminosulfonyl group, a diethylaminosulfonyl group, or an alkylgroup of 1 to 4 carbons substituted with 1 or 2 groups selected fromamong phenyl, heterocycles, phenoxy, —O-Het (wherein Het represents aheterocycle) and hydroxyl, —NH—CO—R¹⁹ (wherein R¹⁹ represents hydrogen,an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, abenzyl group, a heterocycle, an alkoxy group of 1 to 4 carbons or abenzyloxy group), —CO—R²⁰ (wherein R²⁰ represents hydrogen, aheterocycle, an alkoxy group of 1 to 4 carbons, a phenoxy group, abenzyloxy group or —OR²¹ (wherein R²¹ represents hydrogen or aheterocycle)) and —CO—NR²²R²³ (wherein R²² and R²³ each independentlyrepresents hydrogen, an alkyl group of 1 to 4 carbons, a benzyl group ora heterocycle).

[0080] When R⁴ is R^(4a), there may be mentioned as specific examples ofR^(4a), hydrogen; nitro; cyano; halogen atoms such as fluorine,chlorine, bromine and iodine; heterocycles such as imidazolyl,thiazolyl, isothiazolyl, pyrazolyl, triazolyl, pyrrolyl, pyridyl,pyrimidinyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolidinyl,oxazolidinyl, imidazolidinyl, 6-oxo-4,5-benzo-1,3-oxazin-2-yl,1-oxoisoindolin-2-yl, pyrrolidinyl, 2,5-dioxopyrrolidinyl, piperidyl,2,6-dioxopiperidyl, 1-(4-bromobenzoyl)piperidin-4-yl, morpholinyl,piperazinyl, 2,3-dioxopiperazinyl, homopiperazinyl, tetrahydrofuryl andtetrahydropyranyl; alkenyl groups such as vinyl, allyl, 1-propenyl,isopropenyl, 2-butenyl, 3-butenyl, 1-pentenyl and 2-pentenyl; alkynylgroups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 2-methyl-3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl and4-pentynyl; aryl groups such as phenyl and naphthyl; hydroxyl;cycloalkyloxy groups such as cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and cycloheptyloxy; aryloxy groups such asphenoxy and naphthyloxy; groups represented by —O-Het (wherein Hetrepresents a heterocycle), such as imidazolyloxy, thiazolyloxy,isothiazolyloxy, pyrazolyloxy, triazolyloxy, pyrrolyloxy, pyridyloxy,pyrimidinyloxy, pyrazinyloxy, furyloxy, thienyloxy, isoxazolyloxy,thiazolidinyloxy, oxazolidinyloxy, imidazolidinyloxy, pyrrolidinyloxy,piperidyloxy, morpholinyloxy, piperazinyloxy, tetrahydrofuryloxy andtetrahydropyranyloxy; optionally halogen-substituted alkylsulfonyloxygroups such as methanesulfonyloxy, ethanesulfonyloxy,n-propanesulfonyloxy and trifluoromethanesulfonyloxy; arylsulfonyloxygroups such as phenylsulfonyloxy and naphthalenesulfonyloxy; acyloxygroups such as formyloxy, acetyloxy, propionyloxy, butyryloxy,isobutyryloxy and trimethylacetyloxy; arylcarboxy groups such asbenzoyloxy and naphthylcarboxy; aralkylcarboxy groups such asphenylacetyloxy, 2-phenylpropionyloxy, 3-phenylbutyryloxy,diphenylacetyloxy and naphthylacetyloxy; groups represented by —O—CO-Het(wherein Het represents a heterocycle), such as imidazolylcarboxy,thiazolylcarboxy, isothiazolylcarboxy, pyrazolylcarboxy,triazolylcarboxy, pyrrolylcarboxy, pyridylcarboxy, pyrimidinylcarboxy,pyrazinylcarboxy, furylcarboxy, thienylcarboxy, isoxazolylcarboxy,thiazolidinylcarboxy, oxazolidinylcarboxy, imidazolidinylcarboxy,pyrrolidinylcarboxy, piperidylcarboxy, morpholinylcarboxy,piperazinylcarboxy, tetrahydrofurylcarboxy and tetrahydropyranylcarboxy;amino; alkylamino groups such as methylamino, dimethylamino, ethylamino,diethylamino, propylamino, dipropylamino, isopropylamino,diisopropylamino and dibutylamino; aralkylamino groups such asbenzylamino and dibenzylamino; heterocycle-substituted amino groups suchas imidazolylamino, N-methyl-N-imidazolylamino, thiazolylamino,N-methyl-N-thiazolylamino, isothiazolylamino, pyrazolylamino,triazolylamino, N-methyl-N-triazolylamino, pyrrolylamino, pyridylamino,N-methyl-N-pyridylamino, dipyridylamino, pyrimidinylamino,pyrazinylamino, furylamino, thienylamino, isoxazolylamino,thiazolidinylamino, oxazolidinylamino, imidazolidinylamino,pyrrolidinylamino, N-methyl-N-pyrrolidinylamino, piperidylamino,morpholinylamino, N-methyl-N-morpholinylamino, tetrahydrofurylamino andtetrahydropyranylamino; optionally halogen-substitutedalkylsulfonylamino groups such as methanesulfonylamino,N-methyl-N-methanesulfonylamino, ethanesulfonylamino,n-propanesulfonylamino and trifluoromethanesulfonylamino;arylsulfonylamino groups such as phenylsulfonylamino,N-methyl-N-phenylsulfonylamino, N-(4-chlorophenylsulfonyl)-N-methylaminoand naphthalenesulfonylamino; acylamino groups such as formylamino,acetylamino, N-methyl-N-acetylamino, propionylamino, butyrylamino,isobutyrylamino, N-methyl-N-isobutyrylamino and trimethylacetylamino;arylcarbonylamino groups such as benzoylamino, N-methyl-N-benzoylaminoand naphthylcarbonylamino; aralkylcarbonylamino groups such asphenylacetylamino, N-methyl-N-phenylacetylamino, 2-phenylpropionylamino,3-phenylbutyrylamino, diphenylacetylamino and naphthylacetylamino; aminogroups substituted with a group represented by —CO-Het (wherein Hetrepresents a heterocycle), such as imidazolylcarbonylamino,N-methyl-N-imidazolylcarbonylamino, thiazolylcarbonylamino,N-methyl-N-thiazolylcarbonylamino, pyridylcarbonylamino,N-methyl-N-pyridylcarbonylamino, pyrimidinylcarbonylamino,N-methyl-N-pyrimidinylcarbonylamino, pyrazinylcarbonylamino,N-methyl-N-pyrazinylcarbonylamino, furylcarbonylamino,thienylcarbonylamino, N-methyl-N-thienylcarbonylamino,N-methyl-N-oxazolylcarbonylamino, N-methyl-N-tetrazolylcarbonylamino,thiazolidinylcarbonylamino, oxazolidinylcarbonylamino,imidazolidinylcarbonylamino, pyrrolidinylcarbonylamino andpiperidylcarbonylamino; alkoxycarbonylamino groups such asmethoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino,isopropoxycarbonylamino, t-butoxycarbonylamino andN-methyl-N-(t-butoxycarbonyl)amino; aryloxycarbonylamino groups such asphenoxycarbonylamino and naphthyloxycarbonylamino;aralkyloxycarbonylamino groups such as benzyloxycarbonylamino,phenethyloxycarbonylamino, phenylpropoxycarbonylamino,benzhydryloxycarbonylamino and naphthylmethoxycarbonylamino; formyl;carboxyl; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl;aryloxycarbonyl groups such as phenoxycarbonyl and naphthyloxycarbonyl;aralkyloxycarbonyl groups such as benzyloxycarbonyl,phenethyloxycarbonyl, phenylpropoxycarbonyl, benzhydryloxycarbonyl andnaphthylmethoxycarbonyl; acyl groups such as acetyl, propionyl, butyryland isobutyryl; arylcarbonyl groups such as benzoyl andnaphthylcarbonyl; groups represented by —CO-Het (wherein Het representsa heterocycle), such as imidazolylcarbonyl, thiazolylcarbonyl,isothiazolylcarbonyl, pyrazolylcarbonyl, triazolylcarbonyl,pyrrolylcarbonyl, pyridylcarbonyl, pyrimidinylcarbonyl,pyrazinylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl,thiazolidinylcarbonyl, oxazolidinylcarbonyl, imidazolidinylcarbonyl,pyrrolidinylcarbonyl, piperidylcarbonyl, morpholinylcarbonyl,piperazinylcarbonyl and 1,3,4-trihydroisoquinon-2-ylcarbonyl; carbamoylgroups such as carbamoyl, methylcarbamoyl, dimethylcarbamoyl,ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl,cyclopropylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl,phenylcarbamoyl, 4-bromo-2-cyanophenylcarbamoyl,N-methyl-N-phenylcarbamoyl, benzylcarbamoyl, N-benzyl-N-methylcarbamoyl,N-methyl-N-phenethylcarbamoyl, dibenzylcarbamoyl, imidazolylcarbamoyl,N-imidazolyl-N-methylcarbamoyl, N-benzimidazolyl-N-methylcarbamoyl,thiazolylcarbamoyl, N-methyl-N-thiazolylcarbamoyl,benzothiazolylcarbamoyl, N-benzothiazolyl-N-methylcarbamoyl,isothiazolylcarbamoyl, oxazolylcarbamoyl, N-methyl-N-oxazolylcarbamoyl,benzoxazolylcarbamoyl, N-benzoxazolyl-N-methylcarbamoyl,pyrazolylcarbamoyl, triazolylcarbamoyl, pyrrolylcarbamoyl,pyridylcarbamoyl, N-methyl-N-pyridylcarbamoyl,N-methyl-N-(pyridylmethyl)carbamoyl, pyrimidinylcarbamoyl,pyrazinylcarbamoyl, furylcarbamoyl, thienylcarbamoyl,isoxazolylcarbamoyl, thiazolidinylcarbamoyl, oxazolidinylcarbamoyl,imidazolidinylcarbamoyl, pyrrolidinylcarbamoyl, piperidylcarbamoyl,tetrahydrofurylcarbamoyl and tetrahydropyranylcarbamoyl; groupsrepresented by A=CH(CH₂)_(n)— (wherein A represents an alicyclicheterocycle, “═” represents a double bond and n represents 0, 1, or 2),such as (3,5-dioxo-2,4-thiazolidinylidene)methyl,(3,5-dioxo-2,4-oxazolidinylidene)methyl,(2,5-dioxoimidazolidin-4-ylidene)methyl,(5-oxo-3-thioxo-2,4-thiazolidinylidene)methyl,(2,4,6-trioxo-3,5-diazaperhydroinylidene)methyl and(3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene)methyl; groupsrepresented by A=CH(CH₂)_(m)O— (wherein A represents an alicyclicheterocycle, “═” represents a double bond and m represents 1, 2, or 3),such as 2-(3,5-dioxo-2,4-thiazolidinylidene)ethoxy,2-(3,5-dioxo-2,4-oxazolidinylidene)ethoxy,2-(2,5-dioxoimidazolidin-4-ylidene)ethoxy,2-(5-oxo-3-thioxo-2,4-thiazolidinylidene)ethoxy,2-(2,4,6-trioxo-3,5-diazaperhydroinylidene)ethoxy and2-(3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene)ethoxy; andgroups represented by A-SO₂—(CH₂)_(m)— (wherein A represents analicyclic heterocycle and m represents 1, 2, or 3), such as(3,5-dioxo-2,4-thiazolidinyl)sulfonylmethyl,(3,5-dioxo-2,4-oxazolidinyl)sulfonylmethyl,(2,5-dioxoimidazolidin-4-yl)sulfonylmethyl, and(5-oxo-3-thioxo-2,4-thiazolidinyl)sulfonylmethyl.

[0081] As preferred groups for R^(4a) there may be specificallymentioned, for example, hydrogen, nitro, cyano, bromine, imidazolyl,thiazolyl, pyridyl, pyrimidinyl, furyl, thienyl, morpholinyl,piperazinyl, hydroxyl, pyrrolidinyloxy, piperidyloxy,methanesulfonyloxy, trifluoromethanesulfonyloxy, phenylsulfonyloxy,acetyloxy, benzoyloxy, imidazolylcarboxy, thiazolylcarboxy,pyridylcarboxy, pyrimidinylcarboxy, pyrazinylcarboxy, dimethylamino,ethylamino, diethylamino, dibenzylamino, imidazolylamino,thiazolylamino, pyridylamino, pyrimidinylamino,N-methyl-N-methanesulfonylamino, phenylsulfonylamino,N-methyl-N-phenylsulfonylamino, N-methyl-N-acetylamino,N-methyl-N-isobutyrylamino, N-methyl-N-benzoylamino,N-methyl-N-phenylacetylamino, N-methyl-N-imidazolylcarbonylamino,N-methyl-N-thiazolylcarbonylamino, N-methyl-N-thienylcarbonylamino,N-methyl-N-oxazolylcarbonylamino, N-methyl-N-tetrazolylcarbonylamino,N-methyl-N-pyridylcarbonylamino, N-methyl-N-pyrazinylcarbonylamino,N-methyl-N-pyrimidinylcarbonylamino, N-methyl-N-(t-butoxycarbonyl)amino,dimethylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl,N-methyl-N-phenylcarbamoyl, N-benzyl-N-methylcarbamoyl,imidazolylcarbamoyl, benzimidazolylcarbamoyl, thiazolylcarbamoyl,N-methyl-N-thiazolylcarbamoyl, benzothiazolylcarbamoyl,isothiazolylcarbamoyl, pyrazolylcarbamoyl, triazolylcarbamoyl,pyrrolylcarbamoyl, pyridylcarbamoyl, N-methyl-N-pyridylcarbamoyl,pyrimidinylcarbamoyl, pyrazinylcarbamoyl, isoxazolylcarbamoyl,piperidylcarbamoyl, 1,3,4-trihydroisoquinolin-2-ylcarbonyl, formyl,carboxyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl, t-butoxycarbonyl, acetyl, benzoyl,(3,5-dioxo-2,4-thiazolidinylidene)methyl,(3,5-dioxo-2,4-oxazolidinylidene)methyl,(2,5-dioxoimidazolidin-4-ylidene)methyl,(5-oxo-3-thioxo-2,4-thiazolidinylidene)methyl,2-(3,5-dioxo-2,4-thiazolidinylidene)ethoxy,2-(3,5-dioxo-2,4-oxazolidinylidene)ethoxy,2-(2,5-dioxoimidazolidin-4-ylidene)ethoxy,2-(5-oxo-3-thioxo-2,4-thiazolidinylidene)ethoxy,(3,5-dioxo-2,4-thiazolidinyl)sulfonylmethyl,(3,5-dioxo-2,4-oxazolidinyl)sulfonylmethyl,(2,5-dioxoimidazolidin-4-yl)sulfonylmethyl and(5-oxo-3-thioxo-2,4-thiazolidinyl)sulfonylmethyl.

[0082] As particularly preferred groups for R^(4a) there may bespecifically mentioned, for example, hydrogen, nitro, cyano, bromine,thienyl, piperazinyl, trifluoromethanesulfonyloxy, phenylsulfonyloxy,acetyloxy, dimethylamino, dibenzylamino,N-methyl-N-methanesulfonylamino, N-methyl-N-phenylsulfonylamino,N-methyl-N-acetylamino, N-methyl-N-isobutyrylamino,N-methyl-N-benzoylamino, N-methyl-N-phenylacetylamino,N-methyl-N-thienylcarbonylamino, N-methyl-N-oxazolylcarbonylamino,N-methyl-N-thiazolylcarbonylamino, N-methyl-N-pyridylcarbonylamino,thiazolylcarbamoyl, benzothiazolylcarbamoyl, benzimidazolylcarbamoyl,N-methyl-N-phenylcarbamoyl, 1,3,4-trihydroisoquinolin-2-ylcarbonyl,methoxycarbonyl, isopropoxycarbonyl, and(3,5-dioxo-2,4-thiazolidinylidene)methyl.

[0083] When R⁴ is R^(4b), there may be mentioned as specific examples ofsubstituents on the alkoxy groups of 1 to 4 carbons for R^(4a), forexample, halogen atoms such as fluorine, chlorine, bromine and iodine;cycloalkyl groups of 3 to 7 carbons such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl; aryl groups of 6 to 10 carbonssuch as phenyl, aminophenyl and naphthyl; heterocycles such asimidazolyl, N-tosylimidazolyl, thiazolyl,2-(morpholinesulfonyl)thiazolyl, isothiazolyl, pyrazolyl, triazolyl,tetrazolyl, pyrrolyl, pyridyl, 2-methoxypyridyl, 5-hydroxypyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl,2-(morpholinesulfonyl)thienyl, oxazolyl, 2-phenyloxazolyl, isoxazolyl,thiazolidinyl, oxazolidinyl, imidazolidinyl, pyrrolidinyl, piperidyl,morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl anddioxolanyl; —OH; alkoxy groups of 1 to 4 carbons such as methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,t-butoxy, n-pentyloxy, isopentyloxy, 3-pentyloxy, 2,2-dimethylpropoxy,n-hexyloxy, 4-methylpentyloxy and 2-ethylbutoxy; aryloxy groups of 6 to10 carbons such as phenoxy and naphthyloxy; benzyloxy; groupsrepresented by —O-Het (wherein Het represents a heterocycle), such aspyridyloxy and piperidyloxy; acyloxy groups of 1 to 5 carbons such asformyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy andtrimethylacetyloxy; arylcarboxy groups of 7 to 11 carbons such asbenzoyloxy and naphthylcarboxy; phenylacetyloxy; groups represented by—O—CO-Het (wherein Het represents a heterocycle), such asimidazolylcarboxy, thiazolylcarboxy, isothiazolylcarboxy,pyrazolylcarboxy, triazolylcarboxy, pyrrolylcarboxy, pyridylcarboxy,pyrimidinylcarboxy, pyrazinylcarboxy, furylcarboxy, thienylcarboxy,isoxazolylcarboxy, thiazolidinylcarboxy, oxazolidinylcarboxy,imidazolidinylcarboxy, pyrrolidinylcarboxy, piperidylcarboxy,morpholinylcarboxy, piperazinylcarboxy, tetrahydrofurylcarboxy andtetrahydropyranylcarboxy; amino; monosubstituted or disubstituted aminogroups such as methylamino, dimethylamino, ethylamino, diethylamino,propylamino, dipropylamino, isopropylamino, diisopropylamino,dibutylamino, benzylamino, dibenzylamino, 2-hydroxy-2-phenethylamino,2-hydroxy-3-phenoxypropylamino, imidazolylamino, thiazolylamino,isothiazolylamino, pyrazolylamino, triazolylamino, pyrrolylamino,pyridylamino, dipyridylamino, pyrimidinylamino, pyrazinylamino,furylamino, thienylamino, isoxazolylamino, thiazolidinylamino,oxazolidinylamino, imidazolidinylamino, pyrrolidinylamino,piperidylamino, tetrahydrofurylamino and tetrahydropyranylamino;optionally halogen-substituted alkylsulfonylamino groups of 1 to 4carbons such as methanesulfonylamino, ethanesulfonylamino,n-propanesulfonylamino and trifluoromethanesulfonylamino;phenylsulfonylamino; acylamino groups of 1 to 5 carbons such asdimethylaminosulfonylamino, methylaminosulfonylamino, formylamino,acetylamino, propionylamino, butyrylamino, isobutyrylamino andtrimethylacetylamino; arylcarbonylamino groups of 7 to 11 carbons suchas benzoylamino and naphthylcarbonylamino; phenylacetylamino; groupsrepresented by —NH—CO-Het (wherein Het represents a heterocycle), suchas imidazolylcarbonylamino, thiazolylcarbonylamino,isoxazolylcarbonylamino, pyridylcarbonylamino, pyrimidinylcarbonylamino,pyrazinylcarbonylamino, furylcarbonylamino, thienylcarbonylamino,pyrrolidinylcarbonylamino, piperidylcarbonylamino andmorpholinylcarbonylamino; alkoxycarbonylamino groups of 2 to 5 carbonssuch as methoxycarbonylamino, ethoxycarbonylamino,n-propoxycarbonylamino, isopropoxycarbonylamino andt-butoxycarbonylamino; benzyloxycarbonylamino; formyl; carboxy;alkoxycarbonyl groups of 2 to 5 carbons such as methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl andt-butoxycarbonyl; phenoxycarbonyl; benzyloxycarbonyl; acyl groups of 2to 5 carbons such as acetyl, propionyl, butyryl and isobutyryl; groupsrepresented by —CO-Het (wherein Het represents a heterocycle) such asimidazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl,pyrazolylcarbonyl, triazolylcarbonyl, pyrrolylcarbonyl, pyridylcarbonyl,pyrimidinylcarbonyl, pyrazinylcarbonyl, furylcarbonyl, thienylcarbonyl,isoxazolylcarbonyl, thiazolidinylcarbonyl, oxazolidinylcarbonyl,imidazolidinylcarbonyl, pyrrolidinylcarbonyl, piperidylcarbonyl,morpholinylcarbonyl and piperazinylcarbonyl; groups represented by—CO—O-Het (wherein Het represents a heterocycle), such aspyridyloxycarbonyl and piperidyloxycarbonyl; and carbamoyl groups suchas carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl,diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl, benzylcarbamoyl,dibenzylcarbamoyl, imidazolylcarbamoyl, thiazolylcarbamoyl,isothiazolylcarbamoyl, pyrazolylcarbamoyl, triazolylcarbamoyl,pyrrolylcarbamoyl, pyridylcarbamoyl, pyrimidinylcarbamoyl,pyrazinylcarbamoyl, furylcarbamoyl, thienylcarbamoyl,isoxazolylcarbamoyl, thiazolidinylcarbamoyl, oxazolidinylcarbamoyl,imidazolidinylcarbamoyl, pyrrolidinylcarbamoyl, piperidylcarbamoyl,tetrahydrofurylcarbamoyl and tetrahydropyranylcarbamoyl.

[0084] As preferred groups for R^(4b) there may be specificallymentioned, for example, saturated or unsaturated alkoxy groups such asmethoxy, 2-propynyloxy, 2-butynyloxy, 3-hexenyloxy, 5-hexenyloxy and2,2-dimethylpropoxy; halogen-substituted alkoxy groups such as2-bromoethoxy and 2-chloroethoxy; cycloalkyl-alkoxy groups such ascyclopentylmethoxy and cyclohexylmethoxy; aryl-alkoxy groups such asbenzyloxy, aminobenzyloxy, chlorobenzyloxy, fluorobenzyloxy,bromobenzyloxy, nitrobenzyloxy, (trifluoromethyl)benzyloxy,dichlorobenzyloxy, dimethylbenzyloxy, methoxybenzyloxy,sulfamoylbenzyloxy, (methylenedioxy)benzyloxy, carboxybenzyloxy,(methoxycarbonyl)benzyloxy, n-butoxybenzyloxy, 3-phenylpropoxy,di(methoxyphenyl)methoxy, 2,2-diphenylethoxy, 1-methyl-1-phenylethoxyand naphthylmethoxy; heterocycle-substituted alkoxy groups such asthienylmethoxy, 2-(morpholinesulfonyl)thienylmethoxy, pyridylmethoxy,(5-hydroxypyridyl)methoxy, (2-methoxypyridyl)methoxy, 2-(pyridyl)ethoxy,pyrazinylmethoxy, pyrimidinylmethoxy, N-tosylimidazolylmethoxy,oxazolylmethoxy, 2-phenyloxazolylmethoxy, thiazolylmethoxy,2-(morpholinesulfonyl)thiazolylmethoxy,(3,5-dioxo-2,4-thiazolidinyl)methoxy, N-methylpiperidylmethoxy,N-t-butoxycarbonylpiperidylmethoxy, N-acetylpiperidylmethoxy,N-methanesulfonylpiperidylmethoxy, (4-oxachroman-2-yl)methoxy,(3,3-dimethyl-2,4-dioxolanyl)methoxy, (1-methyl-3-oxetanyl)methoxy and2-(morpholin-4-yl)ethoxy; alkoxy-alkoxy groups such as methoxymethyl and2-ethoxyethoxy; benzyloxy-alkoxy groups such as 2-(benzyloxy)ethoxy;acyloxy-alkoxy groups such as 2-(acetyloxy)ethoxy; alkylamino-alkoxygroups such as bis(dimethylaminomethyl)methoxy;alkoxycarbonylamino-alkoxy groups such as4-(t-butoxycarbonylamino)butoxy; and alkoxycarbonyl-alkoxy groups suchas ethoxycarbonylmethoxy, 2-(methoxycarbonyl)ethoxy and5-(ethoxycarbonyl)pentyloxy.

[0085] As particularly preferred groups for R^(4b) there may bespecifically mentioned, for example, methoxy, 2-propynyloxy, benzyloxy,aminobenzyloxy, chlorobenzyloxy, fluorobenzyloxy,(trifluoromethyl)benzyloxy, dichlorobenzyloxy, dimethylbenzyloxy,methoxybenzyloxy, sulfamoylbenzyloxy, (methylenedioxy)benzyloxy,carboxybenzyloxy, (methoxycarbonyl)benzyloxy, n-butoxybenzyloxy,thienylmethoxy, 2-(morpholinesulfonyl)thienylmethoxy, pyridylmethoxy,(2-methoxypyridyl)methoxy, (5-hydroxypyridyl)methoxy, 2-(pyridyl)ethoxy,pyrazinylmethoxy, pyrimidinylmethoxy, N-tosylimidazolylmethoxy,oxazolylmethoxy, 2-phenyloxazolylmethoxy, thiazolylmethoxy,2-(morpholinesulfonyl)thiazolylmethoxy,(3,5-dioxo-2,4-thiazolidinyl)methoxy, N-methylpiperidylmethoxy andmethoxymethyl.

[0086] When R⁴ is R^(4c), there may be mentioned as specific examples ofsubstituents on the alkoxy groups of 1 to 4 carbons for R^(4c), forexample, halogen atoms such as fluorine, chlorine, bromine, iodine;cycloalkyl groups of 3 to 7 carbons such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl; aryl groups of 6 to 10 carbonssuch as phenyl and naphthyl; heterocycles such as imidazolyl, thiazolyl,isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl,oxazolyl, isoxazolyl, thiazolidinyl, oxazolidinyl,3,5-dioxooxazolidinyl, imidazolidinyl, 2-oxoimidazolidinyl,pyrrolidinyl, piperidyl, morpholinyl, pyrazolidinyl,3,5-dioxopyrazolidinyl, piperazinyl, 2,5-dioxopiperazinyl,tetrahydrofuryl, tetrahydropyranyl and dioxolanyl; —SH; —OH; alkoxygroups of 1 to 4 carbons such as methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy,3-pentyloxy, 2,2-dimethylpropoxy, n-hexyloxy, 4-methylpentyloxy and2-ethylbutoxy; aryloxy groups of 6 to 10 carbons such as phenoxy andnaphthyloxy; benzyloxy; groups represented by —O-Het (wherein Hetrepresents a heterocycle), such as pyridyloxy and piperidyloxy; acyloxygroups of 1 to 5 carbons such as formyloxy, acetyloxy, propionyloxy,butyryloxy, isobutyryloxy and trimethylacetyloxy; arylcarboxy groups of7 to 11 carbons such as benzoyloxy and naphthylcarboxy; phenylacetyloxy;groups represented by —O—CO-Het (wherein Het represents a heterocycle),such as imidazolylcarboxy, thiazolylcarboxy, isothiazolylcarboxy,pyrazolylcarboxy, triazolylcarboxy, pyrrolylcarboxy, pyridylcarboxy,pyrimidinylcarboxy, pyrazinylcarboxy, furylcarboxy, thienylcarboxy,isoxazolylcarboxy, thiazolidinylcarboxy, oxazolidinylcarboxy,imidazolidinylcarboxy, pyrrolidinylcarboxy, piperidylcarboxy,morpholinylcarboxy, piperazinylcarboxy, tetrahydrofurylcarboxy andtetrahydropyranylcarboxy; amino; monosubstituted or disubstituted aminogroups such as methylamino, dimethylamino, ethylamino,2-hydroxy-2-phenethylamino, 2-hydroxy-3-phenoxypropylamino,diethylamino, propylamino, dipropylamino, isopropylamino,diisopropylamino, dibutylamino, benzylamino, dibenzylamino,imidazolylamino, thiazolylamino, isothiazolylamino, pyrazolylamino,triazolylamino, pyrrolylamino, pyridylamino, dipyridylamino,pyrimidinylamino, pyrazinylamino, furylamino, thienylamino,isoxazolylamino, thiazolidinylamino, oxazolidinylamino,imidazolidinylamino, pyrrolidinylamino, piperidylamino,tetrahydrofurylamino and tetrahydropyranylamino; optionallyhalogen-substituted alkylsulfonylamino groups of 1 to 4 carbons such asmethanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino andtrifluoromethanesulfonylamino; phenylsulfonylamino; acylamino groups of1 to 5 carbons such as formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino and trimethylacetylamino;arylcarbonylamino groups of 7 to 11 carbons such as benzoylamino,4-chlorobenzoylamino and naphthylcarbonylamino; phenylacetylamino;groups represented by —NH—CO-Het (wherein Het represents a heterocycle),such as imidazolylcarbonylamino, thiazolylcarbonylamino,pyridylcarbonylamino, pyrimidinylcarbonylamino, pyrazinylcarbonylamino,furylcarbonylamino, thienylcarbonylamino, thiazolidinylcarbonylamino,oxazolidinylcarbonylamino, imidazolidinylcarbonylamino,pyrrolidinylcarbonylamino and piperidylcarbonylamino;alkoxycarbonylamino groups of 2 to 5 carbons such asmethoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino,isopropoxycarbonylamino and t-butoxycarbonylamino;benzyloxycarbonylamino; formyl; carboxyl; alkoxycarbonyl groups of 2 to5 carbons such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl and t-butoxycarbonyl; phenoxycarbonyl;benzyloxycarbonyl; acyl groups of 2 to 5 carbons such as acetyl,propionyl, butyryl and isobutyryl; groups represented by —CO-Het(wherein Het represents a heterocycle), such as imidazolylcarbonyl,thiazolylcarbonyl, isothiazolylcarbonyl, pyrazolylcarbonyl,triazolylcarbonyl, pyrrolylcarbonyl, pyridylcarbonyl,pyrimidinylcarbonyl, pyrazinylcarbonyl, furylcarbonyl, thienylcarbonyl,isoxazolylcarbonyl, thiazolidinylcarbonyl, oxazolidinylcarbonyl,imidazolidinylcarbonyl, pyrrolidinylcarbonyl, piperidylcarbonyl,morpholinylcarbonyl and piperazinylcarbonyl; groups represented by—CO—O-Het (wherein Het represents a heterocycle), such aspyridyloxycarbonyl and piperidyloxycarbonyl; and carbamoyl groups suchas carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl,diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl, benzylcarbamoyl,dibenzylcarbamoyl, imidazolylcarbamoyl, thiazolylcarbamoyl,isothiazolylcarbamoyl, pyrazolylcarbamoyl, triazolylcarbamoyl,pyrrolylcarbamoyl, pyridylcarbamoyl, pyrimidinylcarbamoyl,pyrazinylcarbamoyl, furylcarbamoyl, thienylcarbamoyl,isoxazolylcarbamoyl, thiazolidinylcarbamoyl, oxazolidinylcarbamoyl,imidazolidinylcarbamoyl, pyrrolidinylcarbamoyl, piperidylcarbamoyl,tetrahydrofurylcarbamoyl and tetrahydropyranylcarbamoyl.

[0087] As preferred groups for R^(4c) there may be specificallymentioned, for example, phenethyl, α-hydroxybenzyl, 1-(acetyloxy)ethyland (3,5-dioxo-2,4-thiazolidinyl)methyl.

[0088] Thus, as specific preferred combinations for R¹, R², R³, and R⁴there may be mentioned those in which, for example, R¹ is methyl, ethyl,or isopropyl, R² is an acetyl or propionyl group substituted with asubstituent selected from the group consisting of phenyl, phenoxy,amino, t-butoxycarbonylamino, benzyloxycarbonylamino,(benzyloxycarbonyl)-N-methylamino, acetylamino, and morpholinylcarbonyl;or hydrogen, acetyl, propionyl, isobutyryl, benzoyl, pyridylcarbonyl,pyrrolidinylcarbonyl, furylcarbonyl, methanesulfonyl, ortrifluoromethanesulfonyl, R³ is methyl, ethyl, isopropyl, n-pentyl,cyclopentylmethyl or benzyl, and R⁴ is hydrogen, nitro, cyano, bromine,thienyl, piperazinyl, trifluoromethanesulfonyloxy, phenylsulfonyloxy,acetyloxy, dimethylamino, dibenzylamino,N-methyl-N-methanesulfonylamino, N-methyl-N-phenylsulfonylamino,N-methyl-N-acetylamino, N-methyl-N-isobutyrylamino,N-methyl-N-benzoylamino, N-methyl-N-phenylacetylamino,N-methyl-N-imidazolylcarbonylamino, N-methyl-N-thiazolylcarbonylamino,N-methyl-N-pyridylcarbonylamino, N-methyl-N-pyrimidinylcarbonylamino,N-methyl-N-pyrazinylcarbonylamino, N-methyl-N-thienylcarbonylamino,N-methyl-N-oxazolylcarbonylamino, N-methyl-N-(t-butoxycarbonyl)amino,thiazolylcarbamoyl, methoxycarbonyl, isopropoxycarbonyl,(3,5-dioxo-2,4-thiazolidinylidene)methyl, methoxy, 2-propynyloxy,benzyloxy, aminobenzyloxy, chlorobenzyloxy, fluorobenzyloxy,(trifluoromethyl)benzyloxy, dichlorobenzyloxy, dimethylbenzyloxy,methoxybenzyloxy, sulfamoylbenzyloxy, (methylenedioxy)benzyloxy,carboxybenzyloxy, (methoxycarbonyl)benzyloxy, n-butoxybenzyloxy,thienylmethoxy, 2-(morpholinesulfonyl)thienylmethoxy, pyridylmethoxy,(2-methoxypyridyl)methoxy, 2-(pyridyl)ethoxy, pyrazinylmethoxy,pyrimidinylmethoxy, N-tosylimidazolylmethoxy, oxazolylmethoxy,2-phenyloxazolylmethoxy, thiazolylmethoxy,2-(morpholinesulfonyl)thiazolylmethoxy,(3,5-dioxo-2,4-thiazolidinyl)methoxy, N-methylpiperidylmethoxy,methoxymethyl, phenethyl, α-hydroxybenzyl, 1-(acetyloxy)ethyl or(3,5-dioxo-2,4-thiazolidinyl)methyl.

[0089] As specific compounds represented by structural formula (I) abovethere may be mentioned those compounds mentioned in the examples of thepresent specification, but additional compounds that may be mentionedincluded the following:

[0090] 6-(benzofuran-2-yl)-3-ethyl-4-hydroxy-5-methyl-2H-pyran-2-one;

[0091] 6-(benzofuran-2-yl)-4-hydroxy-5-methyl-3-n-propyl-2H-pyran-2-one;

[0092] 4-acetyloxy-6-(benzofuran-2-yl)-5-ethyl-3-methyl-2H-pyran-2-one;

[0093]4-acetyloxy-6-(benzofuran-2-yl)-5-isopropyl-3-methyl-2H-pyran-2-one;

[0094]6-(benzofuran-2-yl)-4-(2-(t-butoxycarbonylamino)acetyloxy)-5-ethyl-3-methyl-2H-pyran-2-one;

[0095]6-(benzofuran-2-yl)-5-ethyl-3-methyl-4-(2-pyrrolidon-5-ylcarboxy)-2H-pyran-2-one;

[0096]4-(2-aminoacetyloxy)-6-(benzofuran-2-yl)-5-ethyl-3-methyl-2H-pyran-2-one;

[0097]4-(3-acetylamino-4-morpholinyl-4-oxobutyryloxy)-6-(benzofuran-2-yl)-5-ethyl-3-methyl-2H-pyran-2-one;

[0098] 6-(benzofuran-2-yl)-3,5-dimethyl-4-propionyloxy-2H-pyran-2-one;

[0099]6-(benzofuran-2-yl)-5-ethyl-4-isobutyryloxy-3-methyl-2H-pyran-2-one;

[0100] 6-(benzofuran-2-yl)-3,5-dimethyl-4-isovaleryloxy-2H-pyran-2-one;

[0101]6-(benzofuran-2-yl)-3,5-dimethyl-4-(2,2,2-trimethylacetyloxy)-2H-pyran-2-one;

[0102]6-(benzofuran-2-yl)-4-cyclohexylcarboxy-3,5-dimethyl-2H-pyran-2-one;

[0103]6-(benzofuran-2-yl)-4-(2-cyclopropylacetyloxy)-3,5-dimethyl-2H-pyran-2-one;

[0104]6-(benzofuran-2-yl)-4-(2-cyclopentylacetyloxy)-3,5-dimethyl-2H-pyran-2-one;

[0105] 6-(benzofuran-2-yl)-4-benzoyloxy-5-ethyl-3-methyl-2H-pyran-2-one;

[0106]6-(benzofuran-2-yl)-4-benzoyloxy-5-isopropyl-3-methyl-2H-pyran-2-one;

[0107]6-(benzofuran-2-yl)-3,5-dimethyl-4-naphthylcarboxy-2H-pyran-2-one;

[0108]6-(benzofuran-2-yl)-3,5-dimethyl-4-imidazolylcarboxy-2H-pyran-2-one;

[0109]6-(benzofuran-2-yl)-3,5-dimethyl-4-thiazolylcarboxy-2H-pyran-2-one;

[0110]6-(benzofuran-2-yl)-3,5-dimethyl-4-triazolylcarboxy-2H-pyran-2-one;

[0111]6-(benzofuran-2-yl)-5-ethyl-3-methyl-4-pyridylcarboxy-2H-pyran-2-one;

[0112]6-(benzofuran-2-yl)-3,5-dimethyl-4-pyrimidinylcarboxy-2H-pyran-2-one;

[0113]6-(benzofuran-2-yl)-3,5-dimethyl-4-pyrazinylcarboxy-2H-pyran-2-one;

[0114] 6-(benzofuran-2-yl)-3,5-dimethyl-4-thienylcarboxy-2H-pyran-2-one;

[0115]6-(benzofuran-2-yl)-3,5-dimethyl-4-isoxazolylcarboxy-2H-pyran-2-one;

[0116]6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-imidazolylacetyloxy)-2H-pyran-2-one;

[0117]6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-pyridylacetyloxy)-2H-pyran-2-one;

[0118]6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-methoxyacetyloxy)-2H-pyran-2-one;

[0119]6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-t-butoxyacetyloxy)-2H-pyran-2-one;

[0120] 6-(benzofuran-2-yl)-4-hydroxy-3-methyl-5-n-propyl-2H-pyran-2-one;

[0121]6-(benzofuran-2-yl)-5-cyclopentyl-4-hydroxy-3-methyl-2H-pyran-2-one;

[0122]6-(benzofuran-2-yl)-5-cyclopropylmethyl-4-hydroxy-3-methyl-2H-pyran-2-one;

[0123]6-(benzofuran-2-yl)-5-cyclohexylmethyl-4-hydroxy-3-methyl-2H-pyran-2-one;

[0124]6-(benzofuran-2-yl)-4-hydroxy-3-methyl-5-naphthylmethyl-2H-pyran-2-one;

[0125] 6-(benzofuran-2-yl)-5-ethoxy-4-hydroxy-3-methyl-2H-pyran-2-one;

[0126]6-(benzofuran-2-yl)-4-hydroxy-5-isopropoxy-3-methyl-2H-pyran-2-one;

[0127]4-acetyloxy-3,5-dimethyl-6-(5-(2-thienyl)benzofuran-2-yl)-2H-pyran-2-one;

[0128] 3,5-dimethyl-6-(5-((3,5-dioxo-2,4-oxazolidinylidene)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0129]3,5-dimethyl-6-(5-((2,5-dioxoimidazolidin-4-ylidene)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0130]3,5-dimethyl-4-hydroxy-6-(5-((5-oxo-3-thioxo-2,4-thiazolidinylidene)methyl)benzofuran-2-yl)-2H-pyran-2-one;

[0131]3,5-dimethyl-4-hydroxy-6-(5-((2,4,6-trioxo-3,5-diazaperhydroinylidene)methyl)benzofuran-2-yl)-2H-pyran-2-one;

[0132]3,5-dimethyl-6-(5-((3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0133] 3,5-dimethyl-6-(5-(2-(3,5-dioxo-2,4-thiazolidinylidene)ethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0134] 3,5-dimethyl-6-(5-(2-(3,5-dioxo-2,4-oxazolidinylidene)ethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0135]3,5-dimethyl-6-(5-(2-(2,5-dioxoimidazolidin-4-ylidene)ethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0136]3,5-dimethyl-4-hydroxy-6-(5-(2-(5-oxo-3-thioxo-2,4-thiazolidinylidene)ethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0137]3,5-dimethyl-4-hydroxy-6-(5-(2-(2,4,6-trioxo-3,5-diazaperhydroinylidene)ethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0138]3,5-dimethyl-6-(5-(2-(3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene)ethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0139] 3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinyl)sulfonylmethyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0140] 3,5-dimethyl-6-(5-((3,5-dioxo-2,4-oxazolidinyl)sulfonylmethyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0141]3,5-dimethyl-6-(5-((2,5-dioxoimidazolidin-4-yl)sulfonylmethyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0142]3,5-dimethyl-4-hydroxy-6-(5-((5-oxo-3-thioxo-2,4-thiazolidinyl)sulfonylmethyl)benzofuran-2-yl)-2H-pyran-2-one;

[0143]3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinyl)methoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0144]3,5-dimethyl-6-(5-((3,5-dioxo-2,4-oxazolidinyl)methoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0145]3,5-dimethyl-6-(5-((2,5-dioxoimidazolidin-4-yl)methoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0146]3,5-dimethyl-4-hydroxy-6-(5-((5-oxo-3-thioxo-2,4-thiazolidinyl)methoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0147]3,5-dimethyl-4-hydroxy-6-(5-((2,4,6-trioxo-3,5-diazaperhydroinyl)methoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0148]3,5-dimethyl-6-(5-((3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinyl)methoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0149] 3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-phenylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-one;

[0150]6-(5-(N-benzyl-N-methylcarbamoyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0151] 3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-pyridylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-one;

[0152] 3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-thiazolylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-one;

[0153] 3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(pyridylmethyl)carbamoyl)benzofuran-2-yl)-2H-pyran-2-one;

[0154] 3,5-dimethyl-4-hydroxy-6-(5-(2-(2-hydroxy-2-phenethylamino)ethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0155]3,5-dimethyl-4-hydroxy-6-(5-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0156]3,5-dimethyl-4-hydroxy-6-(5-(2-hydroxy-3-aminopropoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0157]3,5-dimethyl-4-hydroxy-6-(5-(2-hydroxy-3-phenylaminopropoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0158] 3,5-dimethyl-4-hydroxy-6-(5-(3-(2-hydroxy-2-phenethylamino)propyl)benzofuran-2-yl)-2H-pyran-2-one;

[0159]3,5-dimethyl-4-hydroxy-6-(5-(3-(2-hydroxy-3-phenoxypropylamino)propyl)benzofuran-2-yl)-2H-pyran-2-one;

[0160]3,5-dimethyl-4-hydroxy-6-(5-(2-(2-hydroxy-2-phenethylamino)ethyl)benzofuran-2-yl)-2H-pyran-2-one;

[0161]3,5-dimethyl-4-hydroxy-6-(5-(2-(2-hydroxy-3-phenoxypropylamino)ethyl)benzofuran-2-yl)-2H-pyran-2-one;

[0162] 3,5-dimethyl-6-(5-(3,5-dioxopyrazolidin-4-ylmethyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0163] 3,5-dimethyl-6-(5-(3,5-dioxooxazolidin-4-ylmethyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0164] 3,5-dimethyl-4-hydroxy-6-(5-(2-oxoimidazolidinylmethyl)benzofuran-2-yl)-2H-pyran-2-one;

[0165]3,5-dimethyl-6-(5-(2,5-dioxopiperazinylmethyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0166]3,5-dimethyl-4-hydroxy-6-(5-(imidazolylmethyl)benzofuran-2-yl)-2H-pyran-2-one;

[0167]6-(5-(N-benzothiazolyl-N-methylcarbamoyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0168]3,5-dimethyl-4-hydroxy-6-(5-(6-oxo-4,5-benzoxazin-2-yl)benzofuran-2-yl)-2H-pyran-2-one;

[0169] 3,5-dimethyl-4-hydroxy-6-(5-(3-pyridylaminomethyl)benzofuran-2-yl)-2H-pyran-2-one;

[0170]6-(5-(4-bromo-2-cyanophenylcarbamoyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0171] 3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(3-pyridyl)aminomethyl)benzofuran-2-yl)-2H-pyran-2-one;

[0172] 3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(3-pyridyl)carbamoyl)benzofuran-2-yl)-2H-pyran-2-one;

[0173] 3,5-dimethyl-4-hydroxy-6-(5-(4-(2-pyridyl)piperazinylcarbonyl)benzofuran-2-yl)-2H-pyran-2-one;

[0174] 3,5-dimethyl-4-hydroxy-6-(5-(4-(2-pyrimidinyl)piperazinylcarbonyl)benzofuran-2-yl)-2H-pyran-2-one;

[0175] 3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(2-pyridyl)carbamoyl)benzofuran-2-yl)-2H-pyran-2-one;

[0176]3,5-dimethyl-4-hydroxy-6-(5-(N-(2-pyrimidinyl)carbamoyl)benzofuran-2-yl)-2H-pyran-2-one;

[0177]3,5-dimethyl-4-hydroxy-6-(5-((2-pyridylmethyl)carbamoyl)benzofuran-2-yl)-2H-pyran-2-one;

[0178]3,5-dimethyl-4-hydroxy-6-(5-(triazolylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-one;

[0179]3,5-dimethyl-6-(5-(2,5-dioxopyrrolidinyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0180]3,5-dimethyl-6-(5-(2,6-dioxopiperidinyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0181]3,5-dimethyl-6-(5-(2,3-dioxopiperazinyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0182]6-(5-(2-(4-chlorobenzoylamino)ethyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0183]6-(5-(3-(acetylamino)propoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0184]3,5-dimethyl-4-hydroxy-6-(5-(3-(2-pyrazinylcarbonylamino)propoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0185]3,5-dimethyl-4-hydroxy-6-(5-(3-(2-pyridylcarbonylamino)propoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0186]3,5-dimethyl-4-hydroxy-6-(5-(3-(5-isoxazolylcarbonylamino)propoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0187]3,5-dimethyl-4-hydroxy-6-(5-(3-(morpholinylcarbonylamino)propoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0188]3,5-dimethyl-4-hydroxy-6-(5-(3-(methanesulfonylamino)propoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0189] 3,5-dimethyl-6-(5-(3-(dimethylaminosulfonylamino)propoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0190]3,5-dimethyl-4-hydroxy-6-(5-(3-(isoxazolylsulfonylamino)propoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0191]6-(5-(N-acetylpiperidin-3-ylmethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0192] 3,5-dimethyl-4-hydroxy-6-(5-(N-(2-pyridylcarbonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0193] 3,5-dimethyl-4-hydroxy-6-(5-(N-(2-pyrazinylcarbonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0194]3,5-dimethyl-4-hydroxy-6-(5-(N-(5-isoxazolylcarbonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0195] 3,5-dimethyl-4-hydroxy-6-(5-(N-(morpholinylcarbonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0196]3,5-dimethyl-4-hydroxy-6-(5-(N-methanesulfonylpiperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0197]3,5-dimethyl-6-(5-(N-(dimethylaminosulfonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0198] 3,5-dimethyl-4-hydroxy-6-(5-(N-(5-thiazolylsulfonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one; and

[0199]3,5-dimethyl-4-hydroxy-6-(5-(N-(5-isoxazolylsulfonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one.

[0200] As preferred specific compounds represented by structural formula(I) above there may be mentioned, for example, the following:

[0201] 4-acetyloxy-6-(benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;

[0202] 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0203] 6-(benzofuran-2-yl)-4-benzoyloxy-3,5-dimethyl-2H-pyran-2-one;

[0204]6-(benzofuran-2-yl)-3,5-dimethyl-4-methanesulfonyloxy-2H-pyran-2-one;

[0205]6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-pyridylcarboxy)-2H-pyran-2-one;

[0206]3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinylidene)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0207]3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinyl)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0208] 6-(benzofuran-2-yl)-4-hydroxy-3-methyl-5-n-pentyl-2H-pyran-2-one;

[0209]3,5-dimethyl-4-hydroxy-6-(5-methoxybenzofuran-2-yl)-2H-pyran-2-one;

[0210]3,5-dimethyl-4-hydroxy-6-(7-methoxybenzofuran-2-yl)-2H-pyran-2-one;

[0211]4-acetyloxy-3,5-dimethyl-6-(6-(trifluoromethanesulfonyloxy)benzofuran-2-yl)-2H-pyran-2-one;

[0212]4-acetyloxy-3,5-dimethyl-6-(6-(2-thienyl)benzofuran-2-yl)-2H-pyran-2-one;

[0213]3,5-dimethyl-4-hydroxy-6-(6-methoxybenzofuran-2-yl)-2H-pyran-2-one;

[0214] 3,5-dimethyl-4-hydroxy-6-(5-(5-pyrimidinylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0215]6-(benzofuran-2-yl)-3,5-dimethyl-4-(4-hydroxymethylbenzoyloxy)-2H-pyran-2-one;

[0216] 6-(benzofuran-2-yl)-4-(2-(N-carbobenzyloxy-N-methylamino)acetyloxy)-3,5-dimethyl-2H-pyran-2-one;

[0217]6-(benzofuran-2-yl)-3,5-dimethyl-4-(4-methoxybenzoyloxy)-2H-pyran-2-one;

[0218]6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-phenylacetyloxy)-2H-pyran-2-one;

[0219] 6-(benzofuran-2-yl)-5-ethyl-4-hydroxy-3-methyl-2H-pyran-2-one;

[0220]6-(benzofuran-2-yl)-4-hydroxy-5-isopropyl-3-methyl-2H-pyran-2-one;

[0221] 6-(benzofuran-2-yl)-5-benzyl-4-hydroxy-3-methyl-2H-pyran-2-one;

[0222] 6-(benzofuran-2-yl)-3,5-dimethyl-4-isobutyryloxy-2H-pyran-2-one;

[0223]4-acetyloxy-3,5-dimethyl-6-(5-nitrobenzofuran-2-yl)-2H-pyran-2-one;

[0224]6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-phenoxyacetyloxy)-2H-pyran-2-one;

[0225] 3,5-dimethyl-4-hydroxy-6-(5-nitrobenzofuran-2-yl)-2H-pyran-2-one;

[0226]3,5-dimethyl-6-(5-(dimethylamino)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0227]6-(5-(dibenzylamino)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0228]3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(2-thienylcarbonyl)amino)benzofuran-2-yl)-2H-pyran-2-one;

[0229]3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(3-pyridylcarbonyl)amino)benzofuran-2-yl)-2H-pyran-2-one;

[0230]3,5-dimethyl-4-hydroxy-6-(5-(N-isobutyryl-N-methylamino)benzofuran-2-yl)-2H-pyran-2-one;

[0231]3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(phenylacetyl)amino)benzofuran-2-yl)-2H-pyran-2-one;

[0232]6-(5-(N-benzoyl-N-methylamino)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0233]6-(5-(N-t-butoxycarbonyl-N-methylamino)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0234]6-(5-(benzothiazolylcarbamoyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0235]6-(5-(benzimidazolylcarbamoyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0236]3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-phenylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-one;

[0237]6-(5-(N-(4-chlorophenylsulfonyl)-N-methylamino)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0238]3,5-dimethyl-4-hydroxy-6-(5-(1,3,4-trihydroisoquinolin-2-ylcarbonyl)benzofuran-2-yl)-2H-pyran-2-one;

[0239]3,5-dimethyl-4-hydroxy-6-(5-morpholinylbenzofuran-2-yl)-2H-pyran-2-one;

[0240]6-(benzofuran-2-yl)-3,5-dimethyl-4-isonicotinoyloxy-2H-pyran-2-one;

[0241]4-(2-aminoacetyloxy)-6-(benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;

[0242] 6-(5-benzyloxybenzofuran-2-yl)-4-(2-(t-butoxycarbonylamino)acetyloxy)-3,5-dimethyl-2H-pyran-2-one;

[0243]4-(2-aminoacetyloxy)-6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;

[0244]4-(4-(acetylamino)benzoyloxy)-6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;

[0245]6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-4-nicotinoyloxy-2H-pyran-2-one;

[0246]6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-4-isonicotinoyloxy-2H-pyran-2-one;

[0247]6-(5-benzyloxybenzofuran-2-yl)-5-ethyl-4-hydroxy-3-methyl-2H-pyran-2-one;

[0248] 5-ethyl-4-hydroxy-3-methyl-6-(5-(3-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0249] 4-acetyloxy-3,5-dimethyl-6-(5-(2-thiazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0250]3,5-dimethyl-4-hydroxy-6-(5-(5-thiazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0251] 4-acetyloxy-6-(5-(2,4-dichloro-5-thiazolylmethoxy)benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;

[0252]3,5-dimethyl-4-hydroxy-6-(5-(2-(4-methyl-5-thiazolyl)ethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0253]4-acetyloxy-3,5-dimethyl-6-(5-(2-(4-methyl-5-thiazolyl)ethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0254]3,5-dimethyl-4-hydroxy-6-(5-(4-methyl-5-thiazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0255]3,5-dimethyl-4-hydroxy-6-(5-(2-(morpholinesulfonyl)-5-thiazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0256]4-acetyloxy-3,5-dimethyl-6-(5-(4-methyl-1-tosyl-5-imidazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0257]6-(benzofuran-2-yl)-3,5-dimethyl-4-(3-phenylpropionyloxy)-2H-pyran-2-one;

[0258] 6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-furoyloxy)-2H-pyran-2-one;

[0259] 6-(benzofuran-2-yl)-3,5-dimethyl-4-nicotinoyloxy-2H-pyran-2-one;

[0260]6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-acetylamino-4-(morpholin-4-yl)-4-oxobutyryloxy)-2H-pyran-2-one;

[0261]4-acetyloxy-6-(5-bromobenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;

[0262]6-(benzofuran-2-yl)-5-cyclopentylmethyl-4-hydroxy-3-methyl-2H-pyran-2-one;

[0263]6-(benzofuran-2-yl)-4-(1-carbobenzyloxy-2-pyrrolidon-5-ylcarboxy)-3,5-dimethyl-2H-pyran-2-one;

[0264]6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-pyrrolidon-5-ylcarboxy)-2H-pyran-2-one;

[0265]6-(benzofuran-2-yl)-4-(2-(t-butoxycarbonylamino)acetyloxy)-3,5-dimethyl-2H-pyran-2-one;

[0266]6-(benzofuran-2-yl)-4-(2,4-dimethoxybenzoyloxy)-3,5-dimethyl-2H-pyran-2-one;

[0267]6-(benzofuran-2-yl)-3,5-dimethyl-4-(3-dimethylaminobenzoyloxy)-2H-pyran-2-one;

[0268]4-(4-(acetylamino)benzoyloxy)-6-(benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;

[0269]3,5-dimethyl-6-(5-(2-fluorobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0270] 3,5-dimethyl-4-hydroxy-6-(5-(3,4-(methylenedioxy)benzyloxy)benzofuran-2-yl)-2H-pyran-2-one;

[0271]3,5-dimethyl-4-hydroxy-6-(5-(3-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0272]3,5-dimethyl-4-hydroxy-6-(5-(5-hydroxy-3-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0273]4-acetyloxy-3,5-dimethyl-6-(5-(2-methoxy-5-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0274]3,5-dimethyl-4-hydroxy-6-(5-(1-methylpiperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0275]6-(5-(4-carboxybenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0276]3,5-dimethyl-4-hydroxy-6-(5-(2-(trifluoromethyl)benzyloxy)benzofuran-2-yl)-2H-pyran-2-one;

[0277]3,5-dimethyl-4-hydroxy-6-(5-(3-(trifluoromethyl)benzyloxy)benzofuran-2-yl)-2H-pyran-2-one;

[0278]6-(5-(3,4-dimethylbenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0279]3,5-dimethyl-4-hydroxy-6-(5-(2-thienylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0280]4-acetyloxy-3,5-dimethyl-6-(5-(2-thienylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0281]3,5-dimethyl-4-hydroxy-6-(5-(3-thienylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0282]3,5-dimethyl-4-hydroxy-6-(5-(2-(morpholinesulfonyl)-5-thienylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0283]4-acetyloxy-3,5-dimethyl-6-(5-(2-(morpholinesulfonyl)-5-thienylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0284]3,5-dimethyl-4-hydroxy-6-(5-(4-oxazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0285] 3,5-dimethyl-4-hydroxy-6-(5-(2-phenyl-4-oxazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;

[0286]6-(5-(2,4-dichlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0287]6-(5-(3,4-dichlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0288]6-(5-(4-n-butoxybenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0289]3,5-dimethyl-4-hydroxy-6-(6-(1,2,3,4-tetrahydronaphthalen-1-yloxy)benzofuran-2-yl)-2H-pyran-2-one;

[0290]3,5-dimethyl-4-hydroxy-6-(5-(2-propyn-1-yloxy)benzofuran-2-yl)-2H-pyran-2-one;

[0291]3,5-dimethyl-6-(5-(3-fluorobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0292]3,5-dimethyl-6-(5-(4-fluorobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;

[0293]3,5-dimethyl-4-hydroxy-6-(5-(3-methoxybenzyloxy)benzofuran-2-yl)-2H-pyran-2-one;

[0294]6-(5-(3-chlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0295]6-(5-(3-aminobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0296]6-(5-(3-(t-butoxycarbonylamino)benzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0297]4-acetyloxy-6-(5-(3-(t-butoxycarbonylamino)benzyloxy)benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;

[0298]4-acetyloxy-3,5-dimethyl-6-(5-trifluoromethanesulfonyloxy-benzofuran-2-yl)-2H-pyran-2-one;

[0299]4-acetyloxy-3,5-dimethyl-6-(5-(methoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one;

[0300]4-acetyloxy-6-(4-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;

[0301]4-acetyloxy-6-(4-acetyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;

[0302]4-acetyloxy-3,5-dimethyl-6-(5-methoxybenzofuran-2-yl)-2H-pyran-2-one;

[0303]4-acetyloxy-6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;

[0304]6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

[0305]4-acetyloxy-3,5-dimethyl-6-(5-p-toluenesulfonyloxy-benzofuran-2-yl)-2H-pyran-2-one;

[0306]4-acetyloxy-6-,(7-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;

[0307]3,5-dimethyl-4-hydroxy-6-(5-(methoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one;

[0308]3,5-dimethyl-4-hydroxy-6-(6-methoxymethoxybenzofuran-2-yl)-2H-pyran-2-one.

[0309] The compounds represented by structural formula (I) above willsometimes form acid addition salts or base addition salts. As specificexamples of acid addition salts there may be mentioned addition salts ofmineral acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid and phosphoric acid; organic acids such as formicacid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid,malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid,malic acid, tartaric acid, citric acid, methanesulfonic acid andethanesulfonic acid; and acidic amino acids such as aspartic acid andglutamic acid; as specific examples of base addition salts there may bementioned salts of metals such as lithium, sodium and potassium; saltsof divalent or trivalent metals such as magnesium, calcium, zinc andaluminum; addition salts of basic amino acids such as lysine andarginine; as well as salts of ammonium and organic ammonium such asmethylammonium, dimethylammonium, trimethylammonium, benzylammonium andmonoethanolammonium. The present invention also encompasses hydrates ofthe compounds represented by structural formula (I), as well as theirvarious solvates and crystal polymorphs.

[0310] The compounds of the invention may generally be produced by theprocesses outlined below in Production Processes 1 to 5, withmodifications if necessary, using readily available starting substances,reagents and common synthesis methods.

[0311] Production Process 1

[0312] Specifically, for example, a benzofuryl-α-pyrone derivative ofthe invention may be produced by the method shown as ProductionProcess 1. A solution, such as a THF solution, of a2,4-disubstituted-β-keto ester is treated with 2 equivalents of a base,for example, 1 equivalent of NaH and 1 equivalent of n-BuLi, or 2equivalents of LDA, to prepare a dienolate, and then abenzofurancarboxylic acid ester derivative is allowed to act thereon forClaisen condensation to obtain a diketo ester intermediate. The diketoester intermediate is subjected to alkali hydrolysis and then acidtreatment to obtain an α-pyrone. The diketo ester intermediate can besubjected to alkali hydrolysis followed by acid treatment and thentreatment with acetic anhydride and pyridine to obtain4-acetyloxy-α-pyrone, and this may be again subjected to alkalihydrolysis to yield 4-hydroxy-α-pyrone. Alternatively, the diketo esterintermediate may be treated with an acid such as sulfuric acid,polyphosphoric acid or p-TsOH or heat treated under reduced pressure, toobtain 4-hydroxy-α-pyrone.

[0313] Production Process 2

[0314] The diketo ester intermediate of Production Process 1 can also beproduced by another method outlined as Production Process 2. Abenzofurylketone is treated with a base such as LDA to prepare anenolate, and this is reacted with a malonic acid ester, such as malonicmonomethyl ester-monochloride, to obtain a diketo ester intermediate.Alternatively, a diketo ester intermediate may be obtained by a processwherein a diketone obtained by reacting an acid chloride or ester with abenzofurylketone enolate is treated with 2 equivalents of a base such asLDA to prepare a dienolate, which is then reacted with a CO₂-relatedcompound such as carbon dioxide gas or dimethyl carbonate.

[0315] Production Process 3

[0316] A benzofuryl-α-pyrone derivative of the invention may also beproduced by the method shown as Production Process 3. Abenzofuryl-α-pyrone derivative can be obtained by a method in which abenzofurylketone is converted to a silylenol ether with TMSCl-Et₃ orTMSOTf-Et₃, for example, and this is reacted with malonic dichloride ora malonic diester.

[0317] Production Process 4

[0318] A benzofuryl-α-pyrone derivative of the invention may also beproduced by the method shown as Production Process 4. Abenzofuryl-α-pyrone derivative can be obtained by a method in which anα-pyrone derivative with a —CH₂X substituent at the 6-carbon (wherein Xrepresents a leaving group such as Cl, Br, I, OMs or OTf) is reactedwith a substituted salicyl aldehyde in the presence of a base such asK₂CO₃ and/or DBU.

[0319] Production Process 5

[0320] Benzofuryl-α-pyrone derivatives of the invention wherein R²(wherein R² represents a group as defined above) is COR⁵ or SO₂R⁶(wherein R⁵ and R⁶ represent groups as defined above) can be produced bythe method shown as Production Process 5. Of the benzofuryl-α-pyronederivatives according to the invention, a benzofuryl-α-pyrone derivativewherein R² is —COR⁵ may be produced by a method wherein a startingmaterial, 6-benzofuryl-4-hydroxy-α-pyrone derivative obtained by any ofProduction Processes 1 to 4 above, with modifications if necessary, isreacted with an acid chloride or acid anhydride in the presence of abase, for example, a tertiary amine such as Et₃N or anitrogen-containing aromatic heterocycle such as pyridine or imidazole,or alternatively, a method wherein the starting material is reacted witha carboxylic acid in the presence of a condensation agent such asWSC—HOBt, DCC—HOBt, CDI, diethyl cyanophosphate or diphenylphosphorylazide, or by a method using the “Mitsunobu reaction” wherein thestarting material is reacted with a carboxylic acid in the presence ofPh₃P-DEAD. Similarly, a benzofuryl-α-pyrone derivative wherein R² isSO₂R⁶ may be produced by reacting a starting material,6-benzofuryl-4-hydroxy-α-pyrone derivative, with a sulfonyl chloridederivative represented by RSO₂Cl, in the presence of a base, forexample, a tertiary amine such as Et₃N or a nitrogen-containing aromaticheterocycle such as pyridine or imidazole.

[0321] Benzofuryl-α-pyrone derivatives of the present invention whereinR⁴ is a substituent as defined above other than hydrogen can be producedby the method shown as Production Process 6 or 7. As shown in ProductionProcess 6, a readily available substituted salicyl aldehyde derivativeis used as the starting material for any of Production Processes 1 to 5above, with modifications if necessary, to obtain a benzofuryl-α-pyrone(route A) or a 2-benzofurancarboxylic acid ester intermediate (route B)substituted with hydroxy, methoxy, formyl, bromo, nitro, etc. Route A isa method involving functional group conversion from the hydroxy,methoxy, formyl, bromo or nitro substituent at the benzofuryl-α-pyronestage, while route B is a method wherein the α-pyrone ring isconstructed after functional group conversion of R⁴ at the2-benzofurancarboxylic acid ester intermediate stage.

[0322] Production Process 6

[0323] Production Process 7

[0324] The functional group conversion of R⁴ from hydroxy, methoxy,formyl, bromo, nitro, etc. can be accomplished by the method shown inProduction Process 7. For the benzofuran-α-pyrone intermediate obtainedby route A in Production Process 6, functional group conversion fromhydroxyl may be accomplished by acylation with an acid chloride or acidanhydride, sulfonylation with sulfonyl chloride or sulfonic anhydride,alkylation by the Mitsunobu reaction, etc.; functional group conversionfrom bromo or trifluoromethanesulfonyloxy may be accomplished bycarbonylation, allylation, cyanation, halogenation, amination, etc. witha transition metal catalyst such as a palladium catalyst, for example;and functional group conversion from formyl may be accomplished byalkylation or acylation with a nucleophilic agent such as anorganometallic reagent or an enolate.

[0325] Functional group conversion of R⁴ from a 2-benzofurancarboxylicacid ester intermediate obtained by route B of Production Process 6 canalso be accomplished using the same method of Production Process 7.

[0326] Production Processes 1 to 7 shown above are not intended torestrict the synthesis processes for the compounds of the invention, andany other processes known in the art may also be used.

[0327] Benzofuryl-α-pyrone derivatives of the invention and their saltsthat are obtained in the manner described above have a triglyceridebiosynthesis inhibiting effect, a blood triglyceride lowering effect anda blood HDL elevating effect, as demonstrated by Examples given below,and can therefore be used as active ingredients, in combination with thecarriers, etc. described below if necessary, to provide pharmaceuticalcompositions, and to provide triglyceride biosynthesis inhibitors, bloodtriglyceride lowering agents or blood HDL elevating agents according tothe invention.

[0328] For clinical application of a benzofuryl-α-pyrone derivative ofthe invention or its salt as a prophylactic or therapeutic agent forhypertriglyceridemia, arteriosclerosis or the like, it may beadministered orally or parenterally such as intrarectally,subcutaneously, intramuscularly, intravenously or percutaneously, butoral or intravenous administration is preferred.

[0329] For oral administration, it may be in the form of a solid orliquid preparation. Solid preparations include tablets, pills, powdersand granules. The active substances in such solid preparations areblended with pharmacologically acceptable carriers such as sodiumbicarbonate, calcium carbonate, potato starch, sucrose, mannitol andcarboxymethyl cellulose. The formulation may be carried out by a commonmethod, and other additives, for example, lubricants such as calciumstearate and magnesium stearate, may also be included for formulation inaddition to the carrier. Enteric coated preparations may also beprepared having an enteric coating formed by spraying theabove-mentioned solid preparations with, for example, an aqueoussolution or an organic solvent solution of an enteric coating substancesuch as cellulose acetate phthalate, hydroxypropylmethyl cellulosephthalate, polyvinyl alcohol phthalate or styrene-maleic anhydridecopolymer, or a methacrylic acid or methyl methacrylate copolymer. Solidpreparations such as powders or granules may also be encapsulated byenteric coated capsules.

[0330] A liquid preparation for oral administration contains, forexample, an emulsifier, solution, suspension, syrup or elixir. Thesepreparations contain conventionally used pharmacologically acceptablecarriers such as water or liquid paraffin. Oily bases such as coconutoil, fractionated coconut oil, soybean oil or corn oil are also used ascarriers. Pharmacologically acceptable carriers also contain, whennecessary, commonly used adjuvants, aromatics, stabilizers orpreservatives. A liquid preparation may be administered in the form of acapsule formed from an absorbable substance such as gelatin. Solidpreparations for intrarectal administration include suppositories thatare produced by known methods to contain the active ingredient.

[0331] A preparation for parenteral administration is administered as asterile aqueous or non-aqueous solution, suspension or emulsion. Anon-aqueous solution or suspension may contain propyl glycol,polyethylene glycol, a vegetable oil such as olive oil or soybean oil oran injectable organic ester such as ethyl oleate, as pharmacologicallyacceptable carriers. Such preparations may also contain adjuvants suchas preservatives, humectants, emulsifiers, dispersers and stabilizers.These solutions, suspensions and emulsions may be sterilized byappropriate means such as, for example, filtration through abacteria-retaining filter, heating, inclusion of a sterilizing agent ortreatment with ultraviolet irradiation. After production and just priorto use of the sterile solid preparation, it may be dissolved in sterilewater or a sterile injection solvent for use. Fatty emulsions preparedby adding water to a uniform solution of the active ingredients with avegetable oil such as soybean oil and a phospholipid such as lecithin,may be homogenized with a homogenizer such as a pressure jet homogenizeror an ultrasonic homogenizer to be used as injections.

[0332] Percutaneous administration dosage forms include ointments,creams and the like. These may be produced by common methods.

[0333] When an active ingredient according to the invention is used as atreatment agent for hypertriglyceridemia or as a prophylactic agent forarteriosclerosis, it may usually be administered at about 1 to 1000 mgper day for adults, though this will depend on the patient's condition,age, gender and body weight and the route of administration. The dosagemay be administered either at one time, or over a few times, such as 2to 6 times, per day.

[0334] The various routes of administration are preferably selectedbased on the absorption efficiency in the body for the particularphysiologically active benzofuryl-α-pyrone derivative, as determined bywell-known pharmacological methods.

EXAMPLES

[0335] The abbreviations used for the derivatives used throughout thepresent specification including the examples, and for the groups withintheir structures and the reagents used, are those commonly used in thefield of organic chemistry; the meanings of the abbreviations are givenbelow.

[0336] THF: tetrahydrofuran, Et₂O: diethyl ether, DMF:N,N-dimethylformamide, AcOEt: ethyl acetate, MeOH: methanol, EtOH:ethanol, DBU: 1,8-diazabicyclo[5.4.0]-7-undecene, DEAD: diethylazodicarboxylate, TMAD: azodicarboxylic acid bis(dimethylamide), DMSO:dimethylsulfoxide, Et₃N: triethylamine, Py: pyridine, n-BuLi:normal-butyllithium, LDA: lithium diisopropylamide, Ac₂O: aceticanhydride, WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride, DCC: 1,3-dicyclohexylcarbodiimide, CDI:carbonyldiimidazole, HOBt: 1-hydroxybenzotriazole, PPTS: pyridiniumpara-toluenesulfonate, TMSOTf: trimethylsilyl trifluoromethanesulfonate,TfOH: trifluoromethanesulfonic acid, Ms: methanesulfonyl, Tf:trifluoromethanesulfonyl, p-Ts: para-toluenesulfonyl, Ph: phenyl, Bu:butyl, Bzl: benzyl, Ac: acetyl, TMS: trimethylsilyl

PRODUCTION EXAMPLES

[0337] Synthesis of Intermediates

[0338] Synthesis of Methyl 2-benzofurancarboxylate

[0339] After adding thionyl chloride (3.80 ml) to a solution of2-benzofurancarboxylic acid (2.00 g) in MeOH (60 ml) at −40° C., themixture was stirred for 19 hours while the temperature graduallyincreased to room temperature. The reaction solution was concentratedunder reduced pressure and the residue was purified by silica gel columnchromatography (n-hexane/AcOEt=6/1) to obtain methyl2-benzofurancarboxylate.

[0340] Yield: 2.16 g (y. 99.2%)

[0341]¹H NMR (δppm, CDCl₃): 3.99 (s, 3H), 7.28 to 7.50 (m, 2H) 7.54 (s,1H), 7.60 (d, J=8.9 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H)

[0342] Synthesis of Methyl 2-methyl-3-oxopentanoate

[0343] Methyl iodide (57 ml) and K₂CO₃ (127 g) were added to a solutionof methyl propionylacetate (100 g) in acetone (800 ml) while cooling onice. The reaction solution was stirred for 96 hours at room temperatureand celite filtered, and then the mother liquor was slowly concentratedunder reduced pressure and distilled under reduced pressure to obtainmethyl 2-methyl-3-oxopentanoate.

[0344] Yield: 105 g (y. 94.8%)

[0345]¹H NMR (δppm, CDCl₃): 1.08 (t, J=7.3 Hz, 3H), 1.35 (d, J=7.3 Hz,3H), 2.45 to 2.72 (m, 2H), 3.54 (q, J=7.3 Hz, 1H), 3.73 (s, 3H)

[0346] Synthesis of Methyl 3-oxononanoate

[0347] Pyridine (11.2 ml) and n-heptanoyl chloride (11.8 ml) were addedto a solution of merudoramu acid (10.0 g) in CHCl₂ (150 ml) at 0° C.,and the mixture was stirred at 0° C. for 30 minutes and then at roomtemperature for 2 hours. The reaction solution was cooled to 0° C.,diluted hydrochloric acid was added and extraction was performed withCH₂Cl₂. The organic layer was rinsed with water and saturated saline,dried with Na₂SO₄ and then filtered and concentrated. MeOH (150 ml) wasadded to the residue prior to heated reflux for 3 hours. After cooling,the reaction solution was concentrated under reduced pressure and theresidue was purified by silica gel column chromatography(n-hexane/AcOEt=13/1) to obtain methyl 3-oxononanoate.

[0348] Yield: 8.51 g (y. 65.9%)

[0349]¹H NMR (δppm, CDCl₃): 0.88 (t, J=6.9 Hz, 3H), 1.22 to 1.40 (m,6H), 1.51 to 1.69 (m, 2H), 2.53 (t, J=7.3 Hz, 2H), 3.45 (s, 2H), 3.74(s, 3H)

[0350] Synthesis of Methyl 2-methyl-3-oxononanoate

[0351] K₂CO₃ (2.67 g) was added to a solution of methyl 3-oxononanoate(3.01 g) and methyl iodide (2.77 g) in acetone (100 ml) and the mixturewas stirred at room temperature for 24 hours. The reaction solution wascelite filtered, and then the mother liquor was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography (n-hexane/AcOEt=13/1) to obtain methyl2-methyl-3-oxononanoate.

[0352] Yield: 3.06 g (y. 94.6%)

[0353]¹H NMR (δppm, CDCl₃): 0.90 (t, J=6.9 Hz, 3H), 1.21 to 1.39 (m,9H), 1.51 to 1.65 (m, 2H), 2.47 to 2.56 (m, 2H), 3.53 (q, J=7.3 Hz, 1H),3.73 (s, 3H)

[0354] Synthesis of Ethyl 2-(benzyloxy)acetate

[0355] Benzyl alcohol (27.5 ml) was added to a suspension of NaH (1.1 g)in Et₂O (250 ml) at 0° C., and after stirring at 0° C. for 10 minutesand at room temperature for 5 minutes, the reaction solution was cooledto −10 to 0° C. and trichloroacetonitrile (27 ml) was added dropwiseover 15 minutes. The reaction solution was stirred for one hour whilethe temperature slowly increased to room temperature, and was thenconcentrated under reduced pressure. A solution of MeOH (1.0 ml) inn-pentane (100 ml) was added to the residue, and the mixture wasvigorously stirred, filtered and concentrated. After then addingn-pentane to the residue and refiltering, the mother liquor wasconcentrated. Et₂O (80 ml), n-pentane (80 ml) and ethyl glycolate (25 g)were added to the residue, and then TfOH (1.5 ml) was added at 0° C. andthe mixture was stirred at 0° C. for 10 minutes and at room temperaturefor 2 hours. The reaction solution was filtered, the mother liquor waspoured into a saturated NaHCO₃ aqueous solution and extraction wasperformed with Et₂O. The organic layer was rinsed with water and driedwith MgSO₄, and then filtered and concentrated. The residue was purifiedby silica gel column chromatography (n-hexane/AcOEt=10/1→6/1) to obtainethyl 2-(benzyloxy)acetate.

[0356] Yield: 38.76 g (y. 83.2%)

[0357]¹H NMR (δppm, CDCl₃): 1.29 (t, J=7.26 Hz, 3H), 4.09 (s, 2H), 4.23(q, J=7.26 Hz, 2H), 4.63 (s, 2H), 7.21 to 7.45 (m, 5H)

[0358] Synthesis of Methyl 6-benzyloxy-2,4-dimethyl-3,5-dioxohexanoate

[0359] A solution of methyl 2-methyl-3-oxopentanoate (13.05 g) in THF(100 ml) was added to a suspension of NaH (3.80 g) in THF (100 ml) at 0°C., and after stirring at 0° C. for 15 minutes, 1.63 M n-BuLi (58 ml)was added and the mixture was stirred at 0° C. for 20 minutes to preparea light yellow dienolate. The reaction solution was cooled to −78° C., asolution of ethyl 2-(benzyloxy) acetate (17.56 g) in THF (30 ml) wasadded, and the mixture was stirred at −78° C. for 5 minutes and then at0° C. for one hour. Diluted hydrochloric acid was poured into thereaction solution for quenching, and extraction was performed with AcOEtat near neutral. The organic layer was rinsed with saturated saline anddried with MgSO₄, and then filtered and concentrated. The residue waspurified by silica gel column chromatography (n-hexane/AcOEt=5/1→3/1) toobtain methyl 6-benzyloxy-2,4-dimethyl-3,5-dioxohexanoate.

[0360] Yield: 9.78 g (y. 37%)

[0361]¹H NMR (δppm, CDCl₃): 1.17 to 1.42 (m, 6H), 3.62 to 3.80 (m, 4H),3.98 to 4.28 (m, 3H), 4.48 to 4.65 (m, 2H), 7.12 to 7.42 (m, 5H)

[0362] Synthesis of4-acetyloxy-6-(benzyloxy)methyl-3,5-dimethyl-2H-pyran-2-one

[0363] An aqueous solution (6 ml) of LiOH-hydrate (64 mg) was added to asolution of methyl 6-benzyloxy-2,4-dimethyl-3,5-dioxohexanoate (430 mg)in THF (10 ml), and the mixture was stirred at room temperature for 1.5hours. The reaction solution was neutralized with diluted hydrochloricacid, and after distilling off the volatile components under reducedpressure, extraction was performed with AcOEt at pH 3. The organic layerwas dried with MgSO₄ and then filtered and concentrated. Ac₂O (6 ml) wasadded to the residue, and after stirring at room temperature for 30minutes, pyridine (4 ml) was added and the mixture was stirred at roomtemperature for one hour. The reaction solution was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (n-hexane/AcOEt=3/1→12/5) to obtain4-acetyloxy-6-(benzyloxy)methyl-3,5-dimethyl-2H-pyran-2-one.

[0364] Yield: 212 mg (y. 47.7%)

[0365]¹H NMR (δppm, CDCl₃): 1.88 (s, 3H), 1.93 (s, 3H), 2.34 (s, 3H),4.35 (s, 2H), 4.58 (s, 2H), 7.23 to 7.41 (m, 5H)

[0366] Synthesis of6-(benzyloxy)methyl-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0367] K₂CO₃ (3.0 g) and water (10 ml) were added to a solution of4-acetyloxy-6-(benzyloxy)methyl-3,5-dimethyl-2H-pyran-2-one (6.08 g) inMeOH (100 ml), and after stirring at room temperature overnight, thereaction solution was celite filtered and the mother liquor wasconcentrated under reduced pressure. Water was added to the residue,extraction was performed with AcOEt, and the organic layer was driedwith Na₂SO₄ and then filtered and concentrated. The residue was purifiedby silica gel column chromatography (n-hexane/AcOEt=5/1→1/1) to obtain6-(benzyloxy)methyl-3,5-dimethyl-4-hydroxy-2H-pyran-2-one.

[0368] Yield: 4.82 g (y. 86%)

[0369] (TLC Rf=0.3; n-hexane/AcOEt=1/1)

[0370] Synthesis of6-(benzyloxy)methyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one

[0371] Diisopropylethylamine (2.1 ml) was added to a solution of6-(benzyloxy)methyl-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (2.60 g) inTHF (50 ml), and after stirring the mixture at room temperature for onehour, chloromethyl methyl ether (921 μl) was added at 0° C. and themixture was stirred at room temperature for one hour. Afterconcentrating the reaction solution under reduced pressure, water wasadded to the residue, extraction was performed with AcOEt, and theorganic layer was dried with Na₂SO₄ and then filtered and concentrated.The residue was purified by silica gel column chromatography(n-hexane/AcOEt=5/1→1/1) to obtain6-(benzyloxy)methyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one.

[0372] Yield: 1.80 g (y. 60%)

[0373] (TLC Rf=0.6; n-hexane/AcOEt=1/1)

[0374] Synthesis of3,5-dimethyl-6-hydroxymethyl-4-methoxymethoxy-2H-pyran-2-one

[0375] 20% Pd(OH)₂/C (360 mg) was added to a solution of6-(benzyloxy)methyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (1.80g) in EtOH (50 ml), and the mixture was vigorously stirred at roomtemperature for 3 hours under a hydrogen gas atmosphere. The reactionsolution was celite filtered and the mother liquor was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (n-hexane/AcOEt=1/1) to obtain3,5-dimethyl-6-hydroxymethyl-4-methoxymethoxy-2H-pyran-2-one.

[0376] Yield: 1.26 g (y. 99%)

[0377] (TLC Rf=0.15; n-hexane/AcOEt=1/1)

[0378] Synthesis of3,5-dimethyl-4-methoxymethoxy-6-(methylsulfonyloxy)methyl-2H-pyran-2-one

[0379] Triethylamine (606 mg) was added to a solution of3,5-dimethyl-6-hydroxymethyl-4-methoxymethoxy-2H-pyran-2-one (1.26 g) inTHF (50 ml), and after stirring the mixture at room temperature for onehour, methanesulfonyl chloride (1.05 g) was added and the mixture wasstirred at room temperature overnight. Water was added to the reactionsolution, extraction was performed with AcOEt, and the organic layer wasdried with Na₂SO₄ and then filtered and concentrated. The residue waspurified by silica gel column chromatography (n-hexane/AcOEt=1/1) toobtain 3,5-dimethyl-4-methoxymethoxy-6-(methylsulfonyloxy)methyl-2H-pyran-2-one.

[0380] Yield: 1.35 g (y. 73%)

[0381] (TLC Rf=0.5; n-hexane/AcOEt=1/1)

[0382] Synthesis of6-bromomethyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one

[0383] Sodium bromide (500 mg) was added to a solution of3,5-dimethyl-4-methoxymethoxy-6-(methylsulfonyloxy)methyl-2H-pyran-2-one(1.35 g) in DMF (20 ml), and after the stirring the mixture at roomtemperature for one hour, the reaction solution was concentrated underreduced pressure. Water was added to the residue, extraction wasperformed with AcOEt, and the organic layer was dried with Na₂SO₄ andthen filtered and concentrated. The residue was purified by silica gelcolumn chromatography (n-hexane/AcOEt=1/1) to obtain6-bromomethyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one.

[0384] Yield: 1.21 g (y. 99%)

[0385] (TLC Rf=0.7; n-hexane/AcOEt=1/1)

[0386] Synthesis of Methyl 6-hydroxybenzofuran-2-carboxylate

[0387] A suspension of 4-methoxysalicyl aldehyde (50 g), K₂CO₃ (65 g)and methyl bromoacetate (65 g) in DMF (500 ml) was stirred at 60° C. forone hour, and after cooling, the reaction solution was concentratedunder reduced pressure. Water was added to the residue, extraction wasperformed with AcOEt, and the organic layer was dried with MgSO₄ andthen filtered and concentrated. Toluene (500 ml) was added to theresidue to make a suspension, and upon addition of DBU (70 g), themixture was stirred at 130° C. overnight. After cooling, the reactionsolution was concentrated under reduced pressure, water was added to theresidue and extraction was performed with AcOEt. The organic layer wasdried with MgSO₄ and then filtered and concentrated. The residue wasdissolved in MeOH (500 ml), concentrated hydrochloric acid (50 ml) wasadded and the mixture was stirred at 60° C. overnight. After cooling,the reaction solution was concentrated under reduced pressure, AcOEt(500 ml) was added to the residue, a saturated NaHCO₃ aqueous solution(500 ml) was slowly added to separate the organic layer and aqueouslayer, and the aqueous layer was extracted with AcOEt. The organic layerwas dried with MgSO₄ and then filtered and concentrated. The residue wasdissolved in CH₂Cl₂ (1000 ml), boron tribromide (125 g) was slowly addedat 0° C., and then the mixture was stirred at room temperature for 24hours. The reaction solution was concentrated under reduced pressure,the resulting brown oil was dissolved in MeOH (500 ml), concentratedhydrochloric acid (50 ml) was further added and the mixture was stirredat 60° C. overnight. After cooling, the reaction solution wasconcentrated under reduced pressure, AcOEt (500 ml) was added to theresidue, a saturated NaHCO₃ aqueous solution (500 ml) was slowly addedto separate the organic layer and aqueous layer, and the aqueous layerwas extracted with AcOEt. The organic layer was dried with MgSO₄ andthen filtered and concentrated.

[0388] The residue was purified by silica gel column chromatography(n-hexane/AcOEt=3/1) to obtain methyl 6-hydroxybenzofuran-2-carboxylate.

[0389] Yield: 37.9 g (y. 60%)

[0390]¹H NMR (δppm, CDCl₃): 3.88 (s, 3H), 5.50 to 6.50 (brs, 1H), 6.80to 7.80 (m, 4H)

[0391] Synthesis of Methyl 6-(benzyloxy)benzofuran-2-carboxylate

[0392] A solution of methyl 6-hydroxybenzofuran-2-carboxylate (3.58 g)in THF (30 ml) was slowly added to a suspension of NaH (800 mg) in THF(100 ml) at room temperature, and after stirring for one hour, DMF (35ml) was added, benzyl bromide (3.77 g) was slowly added and the mixturewas stirred for one hour. Water was added to the reaction solution,extraction was performed with AcOEt, and the organic layer was driedwith MgSO₄ and then filtered and concentrated. The residue was purifiedby silica gel column chromatography (n-hexane/AcOEt 10/1) to obtainmethyl 6-(benzyloxy)benzofuran-2-carboxylate.

[0393] Yield: 4.85 g (y. 95%)

[0394]¹H NMR (δppm, CDCl₃): 3.95 (s, 3H), 5.19 (s, 2H), 6.85 (dd, J=8.1Hz, 2.0 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 7.43 (s, 1H), 7.51 (d, J=8.1Hz, 1H)

[0395] Synthesis of 2-hydroxy-4-morpholinobenzaldehyde

[0396] After slowly adding a solution of 3-morpholinophenol (5.0 g) inTHF (100 ml) to a 3 M diethyl ether solution (10 ml) of ethylmagnesiumbromide, the mixture was stirred at 30° C. for 1.5 hours.Paraformaldehyde (3.0 g) and Et₃N (3.0 g) were added to the reactionsolution and the mixture was stirred at 80° C. for 4 hours. Aftercooling, a 6 N hydrochloric acid aqueous solution (20 ml) was added, themixture was stirred for an hour, and then the organic layer and aqueouslayer were separated and the aqueous layer was rendered weakly alkalineprior to extraction with AcOEt. The organic layers were combined anddried with MgSO₄, and then filtered and concentrated. The residue waspurified by silica gel column chromatography (n-hexane/AcOEt=3/1) toobtain 2-hydroxy-4-morpholinobenzaldehyde.

[0397] Yield: 3.57 g (y. 62%)

[0398]¹H NMR (δppm, CDCl₃): 3.30 (t, J=4.8 Hz, 4H), 3.84 (t, J=4.8 Hz,4H), 6.18 (d, J=2.1 Hz, 1H), 6.55 (dd, J=8.9 Hz, 2.1 Hz, 1H), 7.78 (d,J=8.9 Hz, 1H), 10.30 (s, 1H)

[0399] Synthesis of Methyl 6-morpholinobenzofuran-2-carboxylate

[0400] Methyl bromoacetate (3.0 g) and K₂CO₃ (3.0 g) were added to asolution of 2-hydroxy-4-morpholinobenzaldehyde (3.5 g) in acetonitrile(100 ml), and after heated reflux for 16 hours, the reaction solutionwas filtered and the mother liquor was concentrated under reducedpressure. MeOH (100 ml) and concentrated hydrochloric acid (10 ml) wereadded to the residue, and after reflux for 5 hours, the reactionsolution was concentrated under reduced pressure. A saturated NaHCO₃aqueous solution (100 ml) was added to the residue prior to extractionwith AcOEt, and the organic layer was dried with MgSO₄ and then filteredand concentrated. The residue was purified by silica gel columnchromatography (n-hexane/AcOEt=5/1) to obtain methyl6-morpholinobenzofuran-2-carboxylate.

[0401] Yield: 3.1 g (y. 71%)

[0402]¹H NMR (δppm, CDCl₃): 3.22 (t, J=4.8 Hz, 4H), 3.80 (t, J=4.8 Hz,4H), 3.95 (s, 3H), 6.96 to 7.00 (m, 2H), 7.44 (s, 1H), 7.53 (d, J=8.6Hz, 1H)

[0403] Synthesis of Methyl 5-formylbenzofuran-2-carboxylate

[0404] K₂CO₃ (30 g) was added to a solution of 5-formylsalicyl aldehyde(25 g) and methyl bromoacetate (30 g) in acetonitrile (500 ml), andafter heated reflux for 24 hours followed by cooling, the reactionsolution was filtered and the mother liquor was concentrated underreduced pressure. A saturated ammonium chloride aqueous solution (100ml) was added to the residue prior to extraction with AcOEt, and theorganic layer was dried with MgSO₄ and then filtered and concentrated.The residue was purified by silica gel column chromatography(n-hexane/AcOEt=5/1) to obtain methyl 5-formylbenzofuran-2-carboxylate.

[0405] Yield: 15 g (y. 44%)

[0406] Mass analysis: [M⁺+H]=205.2

[0407] Synthesis of Methyl 5-(dimethoxymethyl)benzofuran-2-carboxylate

[0408] Methyl orthoformate (1.0 g) and polymer-bound PPTS (1.0 g) wereadded to a solution of methyl 5-formylbenzofuran-2-carboxylate (15 g) inMeOH (100 ml), and after allowing the mixture to stand at roomtemperature for 8 hours, the reaction solution was filtered and themother liquor was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane/AcOEt=9/1) toobtain methyl 5-(dimethoxymethyl)benzofuran-2-carboxylate.

[0409] Yield: 10 g (y. 54%)

[0410]¹H NMR (δppm, CDCl₃): 3.35 (s, 3H), 3.98 (s, 3H), 5.49 (s, 1H),7.53 to 7.61 (m, 3H), 7.81 (s, 1H)

[0411] The following compound was produced by a process similar to thepreceding production example, using organic chemical techniqueswell-known to those skilled in the art.

[0412] Ethyl 5-bromobenzofuran-2-carboxylate

[0413]¹H NMR (δppm, CDCl₃): 1.43 (t, J=7.3 Hz, 3H), 4.45 (q, J=7.3 Hz,2H), 7.45 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.54 (dd, J=8.4 Hz, 2.2 Hz,1H), 7.82 (d, J=2.2 Hz, 1H)

Example 1 Synthesis of4-acetyloxy-6-(benzofuran-2-yl-1,5-dimethyl-2H-pyran-2-one

[0414] After adding 60% NaH (220 mg) to a solution of methyl2-methyl-3-oxopentanoate (750 mg) in THF (5 ml) at 0° C. and stirring at0° C. for 5 minutes, the mixture was cooled to −78° C. To this reactionsolution there was added 1.63 M n-BuLi (3.3 ml), and the mixture wasstirred at −78° C. for 30 minutes to prepare a dienolate. A solution ofmethyl 2-benzofurancarboxylate (300 mg) in THF (10 ml) was added to thedienolate, and the mixture was stirred at −78° C. for 20 minutes. Thereaction solution was allowed to return to 0° C., aqueous KHSO₄ wasadded for quenching, and extraction was performed with AcOEt. Theorganic layer was rinsed with saturated saline and dried with MgSO₄, andthen filtered and concentrated. The residue was crudely purified bysilica gel column chromatography (n-hexane/AcOEt=3/1→2/1) to obtainmethyl 5-(benzofuran-2-yl)-2,4-dimethyl-3,5-dioxopentanoate.

[0415] Yield: 433 mg (mixture)

[0416] An aqueous solution (30 ml) of LiOH-hydrate (2.62 g) was added toa solution of 5-(benzofuran-2-yl)-2,4-dimethyl-3,5-dioxopentanoate(14.98 g) in MeOH (50 ml), and after stirring at room temperature for 20minutes, the MeOH was distilled off under reduced pressure. The aqueoussolution of the residue was rinsed with Et₂O and then cooled on ice, anda KHSO₄ aqueous solution was added for adjustment to pH 2.0 to 2.5. Theprecipitated crystals were filtered off and rinsed with water. Themother liquor was saturated with saline and extracted with AcOEt, andthe organic layer was concentrated. The residue was combined with thefiltered off crystals, and after adding pyridine (40 ml) and Ac₂O (40ml), the mixture was stirred at room temperature for 3.5 hours. Thereaction solution was concentrated under reduced pressure and theresidue was recrystallized from n-hexane/AcOEt=3/1 to obtain4-acetyloxy-6-(benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one.

[0417] Yield: 6.11 g (y. 47.3%)

[0418]¹H NMR (δppm, CDCl₃): 2.00 (s, 3H), 2.31 (s, 3H), 2.40 (s, 3H),7.23 to 7.42 (m, 2H), 7.36 (s, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.65 (d,J=7.6 Hz, 1H)

Example 2 Synthesis of6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0419] An aqueous solution (30 ml) of LiOH-hydrate (465 mg) was added toa solution of4-acetyloxy-6-(benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one (3.00 g) inMeOH (100 ml) at 0° C., and after stirring at room temperature for 2hours, the MeOH was distilled off under reduced pressure. The residuewas rinsed with Et₂O, and then a KHSO₄ aqueous solution was added at 0°C. for adjustment to pH 2.0. The precipitated crystals were filtered offand thoroughly rinsed with water and Et₂O in that order and then driedto obtain 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one.

[0420] Yield: 2.54 g (y. 98.5%)

[0421]¹H NMR (δppm, DMSO-d6): 1.93 (s, 3H), 2.28 (s, 3H), 7.28 to 7.47(m, 2H), 7.39 (s, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.74 (d, J=7.3 Hz, 1H),10.91 (brs, 1H)

Example 3 Synthesis of6-(benzofuran-2-yl)-4-benzoyloxy-3,5-dimethyl-2H-pyran-2-one

[0422] Pyridine (64 μl) and benzoyl chloride (45 μl) were added to asuspension of 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one(40 mg) in CH₂Cl₂ (5 ml), and the mixture was stirred at roomtemperature for 50 minutes. The reaction solution was poured into aKHSO₄ aqueous solution and extracted with AcOEt, and the organic layerwas rinsed with saturated saline and dried with MgSO₄, and then filteredand concentrated. The residue was purified by silica gel columnchromatography (n-hexane/AcOEt=5/1→4/1) to obtain6-(benzofuran-2-yl)-4-benzoyloxy-3,5-dimethyl-2H-pyran-2-one.

[0423] Yield: 48 mg (y. 71.2%) Light yellow crystals.

[0424]¹H NMR (δppm, CDCl₃): 2.04 (s, 3H), 2.35 (s, 3H), 7.24 to 7.42 (m,3H), 7.49 to 7.77 (m, 5H), 8.23 (d, J=7.3 Hz, 2H)

Example 4 Synthesis of6-(benzofuran-2-yl)-3,5-dimethyl-4-methanesulfonyl oxy-2H-pyran-2-one

[0425] Et₃N (130 μl) and methanesulfonyl chloride (24 μl) were added toa suspension of6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (40 mg) in THF(5 ml), and the mixture was stirred at room temperature for one hour.The reaction solution was poured into aqueous KHSO₄ and extracted withAcOEt, and the organic layer was rinsed with saturated saline and driedwith MgSO₄, and then filtered and concentrated. The residue was purifiedby silica gel column chromatography (n-hexane/AcOEt=2/1) to obtain6-(benzofuran-2-yl)-3,5-dimethyl-4-methanesulfonyloxy-2H-pyran-2-one.

[0426] Yield: 46 mg (y. 88.2%) Yellow crystals.

[0427]¹H NMR (δppm, CDCl₃): 2.22 (s, 3H), 2.50 (s, 3H), 3.39 (s, 3H),7.26 to 7.44 (m, 3H), 7.54 (d, J=8.2 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H)

Example 5 Synthesis of6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-pyridylcarboxy)-2H-pyran-2-one

[0428] WSC (43 mg) was added to a solution of6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (40 mg),picolinic acid (23 mg) and HOBt (21 mg) in DMF (3 ml), and the mixturewas stirred at room temperature for 21.5 hours. The reaction solutionwas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (n-hexane/AcOEt=2/1→3/2) to obtain6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-pyridylcarboxy)-2H-pyran-2-one.

[0429] Yield: 30 mg (y. 53.2%) Light yellow crystals.

[0430]¹H NMR (δppm, CDCl₃) 2.07 (s, 3H), 2.38 (s, 3H), 7.25 to 7.42 (m,3H), 7.53 (d, J=8.2 Hz, 1H), 7.61 to 7.69 (m, 2H),7.99 (dd, J=1.6 Hz,7.9 Hz, 1H), 8.32 (d, J=7.9 Hz, 1H), 8.90 (d, J=4.6 Hz, 1H)

Example 6 Synthesis of3,5-dimethyl-4-hydroxy-6-(6-morpholinylbenzofuran-2-yl)-2H-pyran-2-one

[0431] A solution of methyl 2-methyl-3-oxopentanoate (865 mg) in THF (30ml) was slowly added to a suspension of NaH (240 mg) in THF (50 ml), andafter stirring for 10 minutes, the mixture was cooled to −78° C. and1.58 M n-BuLi (3.8 ml) was slowly added dropwise. After stirring thereaction solution at −78° C. for 30 minutes, a solution of methyl6-morpholinylbenzofuran-2-carboxylate (1.3 g) in THF (15 ml) was slowlyadded and the mixture was stirred at −78° C. for 4 hours. A saturatedammonium chloride aqueous solution (30 ml) was added to the reactionsolution, and after bringing it to room temperature, extraction wasperformed with AcOEt and the organic layer was dried with MgSO₄ and thenfiltered and concentrated. The residue was dissolved in MeOH (30 ml) andTHF (30 ml), a 4 N lithium hydroxide aqueous solution (10 ml) was added,and after stirring at room temperature for 4 hours, a saturated KHSO₄aqueous solution (50 ml) was slowly added. The deposited yellowprecipitate was filtered off and rinsed with AcOEt to obtain3,5-dimethyl-4-hydroxy-6-(6-morpholinylbenzofuran-2-yl)-2H-pyran-2-one.

[0432] Yield: 1.40 g (y. 82%)

[0433]¹H NMR (δppm, DMSO-d6): 1.92 (s, 3H), 2.26 (s, 3H), 3.19 (t, J=4.8Hz, 4H), 3.75 (t, J=4.8 Hz, 4H), 7.05 (d, J=8.4 Hz, 1H), 7.16 (s, 1H),7.25 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 10.8 (s, 1H)

Example 7 Synthesis of3,5-dimethyl-6-(5-formylbenzofuran-2-yl)-4-hydroxy 2H-pyran-2-one

[0434] A solution of methyl 2-methyl-3-oxopentanoate (7.5 g) in THF (50ml) was slowly added to a suspension of NaH (2.1 g) in THF (200 ml), andafter stirring for 10 minutes, the mixture was cooled to −78° C. and1.58 M n-BuLi (32 ml) was slowly added dropwise. After stirring thereaction solution at −78° C. for 30 minutes, a solution of methyl5-(dimethoxymethyl)benzofuran-2-carboxylate (10 g) in THF (50 ml) wasslowly added and the mixture was stirred at −78° C. for 4 hours. Asaturated ammonium chloride aqueous solution (30 ml) was added to thereaction solution, and after bringing it to room temperature, extractionwas performed with AcOEt and the organic layer was dried with MgSO₄ andthen filtered and concentrated. The residue was dissolved in MeOH (100ml) and THF (100 ml), a 4 N lithium hydroxide aqueous solution (25 ml)was added, and after stirring at room temperature for 4 hours, asaturated KHSO₄ aqueous solution (50 ml) was slowly added. The depositedyellow precipitate was filtered off and rinsed with AcOEt to obtain3,5-dimethyl-6-(5-formylbenzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0435] Yield: 10.8 g (y. 95%)

[0436]¹H NMR (δppm, DMSO-d6): 1.87 (s, 3H), 2.23 (s, 3H), 7.51 (s, 1H),7.78 to 7.92 (m, 2H), 8.28 (s, 1H), 10.0 (s, 1H)

Example 8 Synthesis of4-acetyloxy-3,5-dimethyl-6-(5-formylbenzofuran-2-yl)-2H-pyran-2-one

[0437] After adding Et₃N (1.7 g) to a suspension of3,5-dimethyl-6-(5-formylbenzofuran-2-yl)-4-hydroxy-2H-pyran-2-one (5.0g) in CH₂Cl₂ (100 ml), the mixture was cooled on ice, acetyl chloride(1.32 g) was added and the mixture was stirred at room temperature forone hour. Water (100 ml) was added to the reaction solution, extractionwas performed with AcOEt, and the organic layer was dried with MgSO₄ andthen filtered and concentrated. The residue was purified by silica gelcolumn chromatography (n-hexane/AcOEt=3/1) to obtain4-acetyloxy-3,5-dimethyl-6-(5-formylbenzofuran-2-yl)-2H-pyran-2-one.

[0438] Yield: 5.1 g (y. 88%)

[0439]¹H NMR (δppm, CDCl₃): 2.02 (s, 3H), 2.32 (s, 3H), 2.41 (s, 3H),7.46 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 8.20 (s,1H), 10.1 (s, 1H)

Example 9 Synthesis of3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinylidene)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0440] Piperidine (100 mg) was added to a solution of4-acetyloxy-3,5-dimethyl-6-(5-formylbenzofuran-2-yl)-2H-pyran-2-one (374mg) and 1,3-thiazolidine-2,4-dione (135 mg) in THF (50 ml), and themixture was subjected to heated reflux for 4 hours. After cooling, a 15%sodium hydroxide aqueous solution (10 ml) was added to the reactionsolution, and then after stirring for one hour it was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (CH₂Cl₂/MeOH=5/1) to obtain3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinylidene)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one.

[0441] Yield: 400 mg (y. 91%)

[0442]¹H NMR (δppm, DMSO-d6): 1.96 (s, 3H), 2.22 (s, 3H), 7.32 (s, 1H),7.45 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 8.12 (s, 1H), 8.24 (s,1H), 10.91 (s, 1H), 12.90 (s, 1H)

Example 10 Synthesis of3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinyl)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0443] To 3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinylidene)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one (350 mg) in a mixedsolvent of EtOH (10 ml) and 1,4-dioxane (10 ml) there was added 10% Pd/C(70 mg), and the mixture was stirred for one day in a hydrogen gasatmosphere. The reaction solution was filtered, the mother liquor wasconcentrated under reduced pressure, and then the residue was purifiedby silica gel column chromatography (CH₂Cl₂/MeOH=5/1) to obtain3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinyl)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one.

[0444] Yield: 352 mg (y. quant.)

[0445]¹H NMR (δppm, DMSO-d6): 1.97 (s, 3H), 2.24 (s, 3H), 3.34 to 3.55(m, 1H), 3.67 to 3.82 (m, 1H), 4.98 to 5.01 (m, 1H), 7.24 (s, 1H), 7.39(d, J=8.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 8.12 (s, 1H), 10.93 (s, 1H),12.20 (s, 1H)

Example 11 Synthesis of6-(benzofuran-2-yl)-4-hydroxy-3-methyl-5-n-pentyl-2H-pyran-2-one

[0446] A solution of methyl 2-methyl-3-oxononanoate (3.06 g) in THF (5ml) was added to a suspension of 60% NaH (608 mg) in THF (30 ml) whilecooling on ice, and the mixture was stirred at 0° C. for 10 minutes andthen at room temperature for 30 minutes. The reaction solution wascooled to −78° C., 1.66 M n-BuLi (9.2 ml) was added, and the mixture wasstirred at −78° C. for 30 minutes to prepare a dienolate. A solution ofmethyl 2-benzofurancarboxylate (1.25 g) in THF (5 ml) was added to thedienolate, and the mixture was stirred at −78° C. for 30 minutes. Thereaction solution was brought to 0° C., an NH₄Cl aqueous solution wasadded for quenching, and extraction was performed with AcOEt. Theorganic layer was rinsed with water and saturated saline in that order,and then dried with Na₂SO₄, filtered and concentrated. The residue wasdissolved in MeOH (50 ml), and after adding 2N-LiOH (30 ml) and stirringat room temperature for 2 hours, 1N—HCl was added at 0° C. to acidity ofapproximately pH 3, and extraction was performed with AcOEt. The organiclayer was rinsed with water and saturated saline in that order, and thendried with Na₂SO₄, filtered and concentrated. Pyridine (20 ml) and Ac₂O(20 ml) were added to the residue, and after stirring the mixture atroom temperature for 5 hours it was concentrated under reduced pressure.The residue was dissolved in MeOH (20 ml), imidazole (483 mg) was addedat 0° C., and after stirring the mixture at 0° C. for 10 minutes andthen at room temperature for 30 minutes, it was concentrated underreduced pressure. AcOEt was added to the residue, and the precipitatedcrystals were filtered off. The crystals were recrystallized from EtOHto obtain6-(benzofuran-2-yl)-4-hydroxy-3-methyl-5-n-pentyl-2H-pyran-2-one.

[0447] Yield: 357.9 mg (y. 16.1%)

[0448]¹H NMR (δppm, DMSO-d6): 0.87 (t, J=6.9 Hz, 3H), 1.28 to 1.60 (m,6H), 1.93 (s, 3H), 2.74 to 2.85 (m, 2H), 7.28 to 7.46 (m, 3H), 7.63 (d,J=8.3 Hz, 1H), 7.75 (d, J=7.3 Hz, 1H), 10.86 (brs, 1H)

Example 12 Synthesis of3,5-dimethyl-4-hydroxy-6-(5-methoxybenzofuran-2-yl)-2H-pyran-2-one

[0449] K₂CO₃ (138 mg) was added to a solution of 5-methoxysalicylaldehyde (152 mg) and6-bromomethyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (277 mg) inDMF (5 ml), and the mixture was stirred at room temperature for 16hours. A 6 N hydrochloric acid aqueous solution was slowly added to thereaction solution, and after stirring for one hour, extraction wasperformed with AcOEt and the organic layer was dried with MgSO₄ and thenfiltered and concentrated. The residue was purified by silica gel columnchromatography (n-hexane/AcOEt=1/1) to obtain3,5-dimethyl-4-hydroxy-6-(5-methoxybenzofuran-2-yl)-2H-pyran-2-one.

[0450] Yield: 229 mg (y. 80%)

[0451]¹H NMR (δppm, CDCl₃): 2.01 (s, 3H), 2.25 (s, 3H), 4.00 (s, 3H),5.50 to 6.50 (brs, 1H), 6.80 to 7.80 (m, 4H)

Example 13 Synthesis of3,5-dimethyl-4-hydroxy-6-(7-methoxybenzofuran-2-yl)-2H-pyran-2-one

[0452]3,5-dimethyl-4-hydroxy-6-(7-methoxybenzofuran-2-yl)-2H-pyran-2-one wasobtained in the same manner as the preceding, example.

[0453] Yield: 78%

[0454]¹H NMR (δppm, CDCl₃): 2.10 (s, 3H), 2.26 (s, 3H), 4.00 (s, 3H),5.50 to 6.50 (brs, 1H), 6.80 to 7.80 (m, 4H)

Example 14 Synthesis of6-(5-aminobenzofuran-2-yl)-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-oneand3,5-dimethyl-6-(5-(ethylamino)benzofuran-2-yl)-4-methoxymethoxy-2H-pyran-2-one

[0455] To a solution of3,5-dimethyl-4-methoxymethoxy-6-(5-nitrobenzofuran-2-yl)-2H-pyran-2-one(100 mg) in dioxane (20 ml) and EtOH (20 ml) there was added 5% Pd/C (5mg), and after displacing the reaction vessel atmosphere with hydrogen,the mixture was stirred at room temperature overnight. The reactionsolution was filtered and concentrated, and then purified by silica gelthin-layer chromatography (n-hexane/AcOEt=1/1) to obtain6-(5-aminobenzofuran-2-yl)-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-oneand3,5-dimethyl-6-(5-(ethylamino)benzofuran-2-yl)-4-methoxymethoxy-2H-pyran-2-one.

[0456]6-(5-aminobenzofuran-2-yl)-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one;

[0457] Yield: 45 mg (y. 49%)

[0458]¹H NMR (δppm, CDCl₃): 2.12 (s, 3H), 2.42 (s, 3H), 3.64 (s, 3H),5.16 (s, 2H), 6.83 (dd, J=2.3 Hz, 8.9 Hz, 1H), 6.96 (d, J=2.3 Hz, 1H),7.20 (s, 1H), 7.33 (d, J=8.9 Hz, 1H), 7.42 (s, 2H)

[0459]3,5-dimethyl-6-(5-(ethylamino)benzofuran-2-yl)-4-methoxymethoxy-2H-pyran-2-one;

[0460] Yield: 33 mg (y. 33%)

[0461]¹H NMR (δppm, CDCl₃): 1.30 (t, J=7.3 Hz, 3H), 2.11 (s, 3H) 2.39(s, 3H), 3.19 (q, J=7.3 Hz, 2H), 3.62 (s, 3H), 5.11 (s, 2H), 6.69 (dd,J=2.3 Hz, 8.9 Hz, 1H), 6.75 (d, J=2.3 Hz, 1H), 7.20 (s, 1H), 7.31 (d,J=8.9 Hz, 1H)

Example 15 Synthesis of6-(5-(acetylamino)benzofuran-2-yl)-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one

[0462] Pyridine (400 μl) and Ac₂O (15 μl) were added to6-(5-aminobenzofuran-2-yl)-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one(45 mg), and after stirring the mixture at room temperature for 6 hours,an NH₄Cl aqueous solution was added and extraction was performed withCH₂Cl₂. The organic layer was dried, filtered and concentrated, and theresidue was purified by silica gel thin-layer chromatography (CH₂Cl₂) toobtain6-(5-acetylamino)benzofuran-2-yl)-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one.

[0463] Yield: 20 mg (y. 39%)

[0464]¹H NMR (δppm, CDCl₃): 2.10 (s, 3H), 2.17 (s, 3H), 2.43 (s, 3H),3.64 (s, 3H), 5.20 (s, 2H), 7.32 (s, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.50(d, J=8.9 Hz, 1H), 7.97 (d, J=0.7 Hz, 1H)

Example 16 Synthesis of6-(5-aminobenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0465] THF (20 ml) was added to and stirred with6-(5-aminobenzofuran-2-yl)-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one(58 mg), one drop of concentrated hydrochloric acid was added and themixture was stirred at room temperature for one hour. The reactionsolution was concentrated under reduced pressure and the residue waspurified by thin-layer chromatography (n-hexane/AcOEt=1/1) to obtain6-(5-aminobenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one.

[0466] Yield: 13 mg (y. 27%)

[0467]¹H NMR (δppm, DMSO-d6): 1.93 (s, 3H), 2.27 (s, 3H), 6.71 (dd,J=2.0 Hz, 8.9 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 7.16 (s, 1H), 7.33 (d,J=8.9 Hz, 1H)

Example 17 Synthesis of6-(6-(benzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-oneand4-acetyloxy-6-(6-(benzyloxy)benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one

[0468] A solution of methyl 2-methyl-3-oxopentanoate (3.24 g) in THF (30ml) was slowly added to a suspension of NaH (900 mg) in THF (50 ml) at0° C., and after stirring for 10 minutes, the mixture was cooled to −78°C. and 1.58 M n-BuLi (14.2 ml) was slowly added dropwise. After stirringthe reaction solution at −78° C. for 30 minutes, a solution of methyl6-(benzyloxy)benzofuran-2-carboxylate (4.26 g) in THF (15 ml) was slowlyadded and the mixture was stirred at −78° C. for 4 hours. A saturatedammonium chloride aqueous solution was added to the reaction solution,and after bringing it to room temperature, extraction was performed withAcOEt and the organic layer was dried with MgSO₄ and then filtered andconcentrated. The residue was dissolved in MeOH (30 ml) and THF (10 ml),a 4 N lithium hydroxide aqueous solution (5 ml) and water (50 ml) wereadded, and after stirring at room temperature for 4 hours, a saturatedKHSO₄ aqueous solution (30 ml) was slowly added. The deposited yellowprecipitate was filtered off and rinsed with AcOEt to obtain6-(6-(benzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one.

[0469] Yield: 964 mg (y. 25%)

[0470]¹H NMR (δppm, DMSO-d6): 2.00 (s, 3H), 2.24 (s, 3H), 5.27 (s, 2H),7.11 (d, J=8.4 Hz, 1H), 7.30 to 7.70 (m, 8H), 10.8 (brs, 1H)

[0471] The filtrate was further concentrated under reduced pressure,water (30 ml) and AcOEt (30 ml) were added, the organic layer andaqueous layer were separated, and the aqueous layer was extracted withAcOEt. The organic layers were combined, dried with MgSO₄, filtered andconcentrated. Acetic anhydride (10 ml) and pyridine (3 ml) were added tothe residue, and after stirring overnight, the reaction solution wasconcentrated under reduced pressure and purified by silica gel columnchromatography (n-hexane/AcOEt=5/1→1/1) to obtain4-acetyloxy-6-(6-(benzyloxy)benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one.

[0472] Yield: 904 mg (y. 21%)

[0473]¹H NMR (δppm, CDCl₃): 1.92 (s, 3H), 1.97 (s, 3H), 2.37 (s, 3H),5.09 (s, 2H), 6.80 to 7.80 (m, 9H)

Example 18 Synthesis of4-acetyloxy-3,5-dimethyl-6-(6-hydroxybenzofuran-2-yl-2H-pyran-2-one

[0474] To a solution of4-acetyloxy-6-(6-(benzyloxy)benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one(500 mg) in EtOH (50 ml) and 1,4-dioxane (50 ml) there was added 10%Pd/C (100 mg), and the mixture was vigorously stirred at roomtemperature for 3 hours under a hydrogen gas atmosphere. The reactionsolution was celite filtered, and then the filtrate was concentratedunder reduced pressure and the residue was purified by silica gel columnchromatography (n-hexane/AcOEt=1/1) to obtain4-acetyloxy-3,5-dimethyl-6-(6-hydroxybenzofuran-2-yl)-2H-pyran-2-one.

[0475] Yield: 388 mg (y. 95%)

[0476]¹H NMR (δppm, CDCl₃): 1.92 (s, 3H), 1.97 (s, 3H), 2.37 (s, 3H),5.50 to 6.50 (brs, 1H), 6.80 to 7.80 (m, 4H)

Example 19 Synthesis of 4-acetyloxy-3,5-dimethyl-6-(6)-(trifluoromethanesulfonyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0477] Pyridine (100 mg) was added to a solution of4-acetyloxy-3,5-dimethyl-6-(6-hydroxybenzofuran-2-yl)-2H-pyran-2-one(385 mg) in CH₂Cl₂ (10 ml), and after stirring at room temperature forone hour, trifluoromethanesulfonic anhydride (415 mg) was slowly addedwhile cooling on ice and the mixture was stirred at room temperature for2 hours. A saturated NaHCO₃ aqueous solution (10 ml) was added to thereaction solution, extraction was performed with AcOEt, and the organiclayer was dried with Na₂SO₄ and then filtered and concentrated. Theresidue was purified by silica gel column chromatography(n-hexane/AcOEt=2/1) to obtain4-acetyloxy-3,5-dimethyl-6-(6-(trifluoromethanesulfonyloxy)benzofuran-2-yl)-2H-pyran-2-one.

[0478] Yield: 392 mg (y. 72%)

[0479] Mass analysis: [M⁺+H]=447.3

Example 20 Synthesis of4-acetyloxy-3,5-dimethyl-6-(6-(methoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one

[0480] After adding a solution of4-acetyloxy-3,5-dimethyl-6-(6-(trifluoromethanesulfonyloxy)benzofuran-2-yl)-2H-pyran-2-one(350 mg) in THF (5 ml) and Et₃N (80 mg) to a mixed solution of palladiumacetate (3.5 mg) and diphenylphospinopropane (6.5 mg) in DMSO (5 ml) andMeOH (5 ml), the mixture was stirred at room temperature for one hourunder a carbon monoxide atmosphere, and then further stirred at 80° C.for 2 hours. The reaction solution was concentrated under reducedpressure and the residue was purified by silica gel columnchromatography (n-hexane/AcOEt=1/1) to obtain4-acetyloxy-3,5-dimethyl-6-(6-(methoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one.

[0481] Yield: 92 mg (y. 33%)

[0482] Mass analysis: [M⁺+H]=357.3

Example 21 Synthesis of6-(6-carboxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0483] A mixed solution of4-acetyloxy-3,5-dimethyl-6-(6-(methoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one(85 mg) and K₂CO₃ (45 mg) in MeOH (5 ml) and H₂O (1 ml) was stirred atroom temperature for one hour, and then the reaction solution wasrendered acidic with a 1 N hydrochloric acid aqueous solution andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (AcOEt/MeOH=5/1) to obtain6-(6-carboxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one.

[0484] Yield: 71 mg (y. quant.)

[0485] Mass analysis: [M⁺+H]=301.2

Example 22 Synthesis of3,5-dimethyl-4-hydroxy-6-(6-(methoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one

[0486] Trimethylsilyldiazomethane (2 M hexane solution, 85 μl) was addedto a mixed solution of6-(6-carboxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (50mg) in MeOH (5 ml) and toluene (1 ml), and the mixture was stirred atroom temperature for 10 minutes. After adding acetic acid to thereaction solution for quenching of the excesstrimethylsilyldiazomethane, it was concentrated under reduced pressure.The residue was purified by silica gel column chromatography(CH₂Cl₂/MeOH=9/1) to obtain3,5-dimethyl-4-hydroxy-6-(6-(methoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one.

[0487] Yield: 50 mg (y. 96%)

[0488] Mass analysis: [M⁺+H]=315.3

Example 23 Synthesis of4-acetyloxy-3,5-dimethyl-6-(6-dimethylaminobenzofuran-2-yl)-2H-pyran-2-one

[0489] Tetrakis(triphenylphosphine)palladium (3 mg) anddimethylaminotrimethyltin (34 mg) were added to a solution of4-acetyloxy-3,5-dimethyl-6-(6-(trifluoromethanesulfonyloxy)benzofuran-2-yl)-2H-pyran-2-one (45 mg) in toluene (5 ml), and themixture was stirred at 50° C. overnight. After cooling, the reactionsolution was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography (n-hexane/AcOEt=5/1) toobtain4-acetyloxy-3,5-dimethyl-6-(6-dimethylaminobenzofuran-2-yl)-2H-pyran-2-one.

[0490] Yield: 9.6 mg (y. 28%)

[0491] Mass analysis: [M⁺+H]=342.3

Example 24 Synthesis of4-acetyloxy-3,5-dimethyl-6-(6-(2-furyl)benzofuran-2-yl)-2H-pyran-2-one

[0492]4-acetyloxy-3,5-dimethyl-6-(6-(2-furyl)benzofuran-2-yl)-2H-pyran-2-onewas obtained in the same manner as the preceding example, using2-(tributylstannyl)furan.

[0493] Yield: 31 mg (y. 87%)

[0494] Mass analysis: [M⁺+H]=365.3

Example 25 Synthesis of4-acetyloxy-3,5-dimethyl-6-(6-(2-thienyl)benzofuran-2-yl)-2H-pyran-2-one

[0495]4-acetyloxy-3,5-dimethyl-6-(6-(2-thienyl)benzofuran-2-yl)-2H-pyran-2-onewas obtained in the same manner as the preceding example, using2-(tributylstannyl)thiophene.

[0496] Yield: 31 mg (y. 85%)

[0497] Mass analysis: [M⁺+H]=381.4

Example 26 Synthesis of3,5-dimethyl-4-hydroxy-6-(6-methoxybenzofuran-2-yl)-2H-pyran-2-one

[0498] K₂CO₃ (1.38 g) was added to a solution of 4-methoxysalicylaldehyde (1.52 g) and6-bromo-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (2.77 g) in DMF (50ml), and after stirring at room temperature overnight, the reactionsolution was concentrated under reduced pressure. Water (50 ml) wasadded to the residue, extraction was performed with AcOEt, and theorganic layer was dried with MgSO₄ and then filtered and concentrated.The residue was purified by silica gel column chromatography(n-hexane/AcOEt=1/1) to obtain 3.46 g of a yellow oil.Diisopropylethylamine (1.29 g) and DMF (20 ml) were added to 1.74 g ofthe yellow oil, prior to heated reflux overnight. After cooling, a 6 Nhydrochloric acid aqueous solution (10 ml) was slowly added to thereaction solution, and the mixture was stirred at room temperature forone hour and then concentrated under reduced pressure. Water (50 ml) wasadded to the residue, extraction was performed with AcOEt, and theorganic layer was dried with MgSO₄ and then filtered and concentrated.The residue was purified by silica gel column chromatography(n-hexane/AcOEt=1/1) to obtain3,5-dimethyl-4-hydroxy-6-(6-methoxybenzofuran-2-yl)-2H-pyran-2-one.

[0499] Yield: 20 mg (y. 1.3%)

[0500]¹H NMR (δppm, CDCl₃): 2.12 (s, 3H), 2.27 (s, 3H), 4.00 (s, 3H),5.50 to 6.50 (brs, 1H), 6.80 to 7.80 (m, 4H)

Example 27 Synthesis of3,5-dimethyl-4-hydroxy-6-(5-(5-pyrimidinylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0501] A solution of tributylphosphine in 2 N THF (0.94 ml) and asolution of TMAD (323 mg) in CH₂Cl₂ (3 ml) were added dropwise to asolution of4-acetyloxy-3,5-dimethyl-6-(5-hydroxybenzofuran-2-yl)-2H-pyran-2-one(118 mg) and 5-hydroxymethylpyrimidine (202 mg) in THF (30 ml) at 0° C.,and the mixture was stirred at room temperature overnight. The reactionsolution was cooled on ice, a 1 N lithium hydroxide aqueous solution (5ml) was added and the mixture was stirred at room temperature for onehour, after which the reaction solution was again cooled on ice, a 1 Nhydrochloric acid aqueous solution (5 ml) and AcOEt were added, theorganic layer and aqueous layer were separated, and the aqueous layerwas further extracted with AcOEt. The organic layers were combined anddried with MgSO₄, and then filtered and concentrated. The residue waspurified by silica gel column chromatography (AcOEt/MeOH=10/1) to obtain3,5-dimethyl-4-hydroxy-6-(5-(5-pyrimidinylmethoxy)benzofuran-2-yl)-2H-pyran-2-one.

[0502] Yield: 35 mg (y. 26%)

[0503]¹H NMR (δppm, DMSO-d6): 1.95 (s, 3H), 2.29 (s, 3H), 5.24 (s, 2H),7.12 to 7.14 (m, 1H), 7.33 to 7.38 (m, 2H), 7.61 to 7.63 (m, 1H), 8.95(s, 2H), 9.18 (s, 1H), 10.91 (brs, 1H)

[0504] The following compounds were produced by processes similar tothose described in the preceding examples and production examples, usingorganic chemical techniques well-known to those skilled in the art.

Example 286-(benzofuran-2-yl)-3,5-dimethyl-4-(4-hydroxymethylbenzoyloxy)-2H-pyran-2-one

[0505]¹H NMR (δppm, CDCl₃): 2.04 (s, 3H), 2.34 (s, 3H), 4,86 (s, 2H),7.24 to 7.42 (m, 3H), 7.53 (d, J=8.2 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H),7.66 (d, J=7.9 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H)

Example 296-(benzofuran-2-yl)-4-(2-(N-carbobenzyloxy-N-methylamino)acetyloxy)-3,5-dimethyl-2H-pyran-2-one

[0506]¹H NMR (δppm, CDCl₃): 1.84, 2.00 (s, 3H), 2.14, 2.32 (s, 3H),3.13, 3.14 (s, 3H), 4.33, 4.36 (s, 2H), 5.18, 5.20 (s, 2H), 7.25 to 7.43(m, 8H), 7.53 (d, J=8.6 Hz, 1H), 7.66 (d, J=6.9 Hz, 1H)

Example 306-(benzofuran-2-yl)-3,5-dimethyl-4-(4-methoxybenzoyloxy)-2H-pyran-2-one

[0507]¹H NMR (δppm, CDCl₃): 2.03 (s, 3H), 2.34 (s, 3H), 3.93 (s, 3H),7.04 (d, J=8.9 Hz, 2H), 7.24 to 7.42 (m, 3H), 7.52 (d, J=8.2 Hz, 1H),7.66 (d, J=7.9 Hz, 1H), 8.17 (d, J=9.2 Hz, 1H)

Example 316-(benzofuran-2-yl)-3,5-dimethyl-4-phenylacetyloxy-2H-pyran-2-one

[0508]¹H NMR (δppm, CDCl₃): 1.86 (s, 3H), 2.14 (s, 3H), 3.93 (s, 2H),7.21 to 7.45 (m, 8H), 7.50 (d, J=7.9 Hz, 1H), 7.63 (d, J=7.9 Hz, 1H)

Example 32 6-(benzofuran-2-yl)-4-hydroxy-3-methyl-2H-pyran-2-one

[0509]¹H NMR (δppm, DMSO-d6): 1.85 (s, 3H), 6.73 (s, 1H), 7.29 to 7.46(m, 3H), 7.67 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.3 Hz, 1H), 11.58 (brs, 1H)

Example 33 6-(benzofuran-2-yl)-5-ethyl-4-hydroxy-3-methyl-2H-pyran-2-one

[0510]¹H NMR (δppm, DMSO-d6): 1.18 (t, J=7.3 Hz, 3H), 1.93 (s, 3H), 2.79(q, J=7.3 Hz, 2H), 7.29 to 7.44 (m, 3H), 7.67 (d, J=8.3 Hz, 1H), 7.74(d, J=8.3 Hz, 1H), 10.89 (brs, 1H)

Example 346-(benzofuran-2-yl)-4-hydroxy-5-isopropyl-3-methyl-2H-pyran-2-one

[0511]¹H NMR (δppm, DMSO-d6): 1.33 (d, J=6.9 Hz, 6H), 1.93 (s, 3H), 3.40to 3.56 (m, 1H), 7.29 to 7.46 (m, 3H), 7.67 (d, J=8.6 Hz, 1H), 7.74 (d,J=7.6 Hz, 1H), 10.85 (s, 1H)

Example 356-(benzofuran-2-yl)-4-hydroxy-3-methyl-5-phenyl-2H-pyran-2-one

[0512]¹H NMR (δppm, DMSO-d6): 2.06 (s, 3H), 6.32 (s, 1H), 7.27 to 7.63(m, 9H), 10.79 (brs, 1H)

Example 366-(benzofuran-2-yl)-5-benzyl-4-hydroxy-3-methyl-2H-pyran-2-one

[0513]¹H NMR (δppm, DMSO-d6): 1.93 (s, 3H), 4.23 (s, 2H), 7.13 to 7.37(m, 8H), 7.62 (d, J=8.3 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 11.01 (brs, 1H)

Example 376-(benzofuran-2-yl)-4-hydroxy-5-methoxy-3-methyl-2H-pyran-2-one

[0514]¹H NMR (δppm, DMSO-d6): 1.92 (s, 3H), 3.82 (s, 3H), 7.32 to 7.51(m, 3H), 7.72 (d, J=7.9 Hz, 1H), 7.78 (d, J=7.3 Hz, 1H), 11.40 (brs, 1H)

Example 386-(benzofuran-2-yl)-4-hydroxy-3-isopropyl-5-methyl-2H-pyran-2-one

[0515]¹H NMR (δppm, DMSO-d6): 1.22 (d, J=6.9 Hz, 6H), 2.29 (s, 3H), 3.20to 3.30 (m, 1H), 7.30 to 7.45 (m, 3H), 7.68 (d, J=7.9 Hz, 1H), 7.74 (d,J=7.6 Hz, 1H), 10.68 (s, 1H)

Example 396-(benzofuran-2-yl)-3,5-dimethyl-4-isobutyryloxy-2H-pyran-2-one

[0516]¹H NMR (δppm, CDCl₃) 1.39 (d, J=6.9 Hz, 6H), 1.98 (s, 3H), 2.29(s, 3H), 2.83 to 3.01 (m, 1H), 7.25 to 7.42 (m, 2H), 7.36 (s, 1H), 7.52(d, J=8.3 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H)

Example 404-acetyloxy-3,5-dimethyl-6-(5-nitrobenzofuran-2-yl)-2H-pyran-2-one

[0517]¹H NMR (δppm, CDCl₃): 2.02 (s, 3H), 2.32 (s, 3H), 2.42 (s, 3H),7.46 (s, 1H), 7.64 (d, J=8.9 Hz, 1H), 8.30 (dd, J=2.3 Hz, 8.9 Hz, 1H),8.59 (d, J=2.3 Hz, 1H)

Example 413,5-dimethyl-4-methoxymethoxy-6-(5-nitrobenzofuran-2-yl)-2H-pyran-2-one

[0518]¹H NMR (δppm, CDCl₃): 2.14 (s, 3H), 2.43 (s, 3H), 3.64 (s, 3H),5.14 (s, 2H), 7.43 (s, 1H), 7.63 (d, J=9.0 Hz, 1H), 8.30 (dd, J=2.1 Hz,9.0 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H)

Example 426-(benzofuran-2-yl)-3,5-dimethyl-4-phenoxyacetyloxy-2H-pyran-2-one

[0519]¹H NMR (δppm, CDCl₃): 1.97 (s, 3H), 2.28 (s, 3H), 4.98 (s, 2H),6.95 to 7.12 (m, 3H), 7.23 to 7.44 (m, 5H), 7.52 (d, J=7.9 Hz, 1H), 7.65(d, J=7.6 Hz, 1H)

Example 436-(benzofuran-2-yl)-3,5-dimethyl-4-trifluoromethanesulfonyloxy-2H-pyran-2-one

[0520]¹H NMR (δppm, CDCl₃): 2.23 (s, 3H), 2.50 (s, 3H), 7.28 to 7.46 (m,3H), 7.55 (d, J=8.2 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H)

Example 446-(benzofuran-2-yl)-3,5-dimethyl-4-paratoluenesulfonyloxy-2H-pyran-2-one

[0521]¹H NMR (δppm, CDCl₃): 1.81 (s, 3H), 2.33 (s, 3H), 2.51 (s, 3H),7.28 to 7.48 (m, 5H), 7.53 (d, J=8.2 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H),7.90 (d, J=8.3 Hz, 2H)

Example 453,5-dimethyl-4-hydroxy-6-(5-nitrobenzofuran-2-yl)-2H-pyran-2-one

[0522]¹H NMR (δppm, CD3OD): 1.96 (s, 3H), 2.32 (s, 3H), 7.61 (s, 1H),7.95 (d, J=9.2 Hz, 1H), 8.30 (dd, J=2.3 Hz, 9.2 Hz, 1H), 8.71 (d, J=2.3Hz, 1H), 11.00 (brs, 1H)

Example 463,5-dimethyl-6-(5-(ethylamino)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0523]¹H NMR (δppm, CD3OD): 1.42 (t, J=7.3 Hz, 3H), 2.04 (s, 3H), 2.43(s, 3H), 3.44 (q, J=7.3 Hz, 2H), 7.37 (s, 1H), 7.50 (dd, J=2.0 Hz, 8.9Hz, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H)

Example 47 3,5-dimethyl-4-hydroxy-6-(5-(p-toluenesulfonylamino)benzofuran-2-yl)-2H-pyran-2-one

[0524]¹H NMR (δppm, CD3OD): 2.00 (s, 3H), 2.36 (s, 6H), 7.07 to 7.11 (m,1H), 7.21 to 7.26 (m, 2H), 7.34 to 7.41 (m, 2H), 7.57 to 7.61 (m, 2H),7.70 to 7.77 (m, 1H)

Example 483,5-dimethyl-6-(5-(dimethylamino)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0525]¹H NMR (δppm, CD3OD): 1.95 (s, 3H), 2.30 (s, 3H), 3.12 (s, 6H),7.41 to 7.75 (m, 4H)

Example 496-(5-(dibenzylamino)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0526]¹H NMR (δppm, CD3OD): 1.94 (s, 3H), 2.31 (s, 3H), 4.65 (s, 4H),6.89 to 6.94 (m, 2H), 7.07 (s, 1H), 7.13 to 7.88 (m, 11H)

Example 506-(benzofuran-2-yl)-3,5-dimethyl-4-isonicotinoyloxy-2H-pyran-2-one

[0527]¹H NMR (δppm, CDCl₃): 2.04 (s, 3H), 2.34 (s, 3H), 7.26 to 7.42 (m,3H), 7.53 (d, J=7.9 Hz, 1H), 7.67 (d, J=7.3 Hz, 1H), 8.03, 8.95 (ABq,J=6.3 Hz, 4H)

Example 514-(2-aminoacetyloxy)-6-(benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-oneHydrochloride

[0528]¹H NMR (δppm, DMSO-d6): 1.96 (s, 3H), 2.27 (s, 3H), 4.41 (s, 2H),7.31 to 7.50 (m, 2H), 7.55 (s, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.78 (d,J=7.9 Hz, 1H), 8.61 (brs, 3H)

Example 52 6-(5-benzyloxybenzofuran-2-yl)-4-(2-(t-butoxycarbonylamino)acetyloxy)-3,5-dimethyl-2H-pyran-2-one

[0529]¹H NMR (δppm, CDCl₃): 1.48 (s, 9H), 2.00 (s, 3H), 2.30 (s, 3H),4.23 (d, J=5.9 Hz, 2H), 5.06 to 5.14 (m, 1H), 5.11 (s, 2H), 7.06 (dd,J=2.6 Hz, 8.9 Hz, 1H), 7.14 (d, J=2.6 Hz, 1H), 7.27 to 7.50 (m, 7H)

Example 534-(2-aminoacetyloxy)-6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-onehydrochloride

[0530]¹H NMR (δppm, DMSO-d6): 1.95 (s, 3H), 2.24 (s, 3H), 4.41 (s, 2H),5.16 (s, 2H), 7.13 (d, J=9.2 Hz, 1H), 7.29 to 7.51 (m, 7H), 7.62 (d,J=9.6 Hz, 1H), 8.57 (brs, 2H)

Example 54 4-(4-(acetylamino)benzoyloxy)-6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one

[0531]¹H NMR (δppm, CDCl₃): 2.02 (s, 3H), 2.26 (s, 3H), 2.31 (s, 3H),5.12 (s, 2H), 7.06 (dd, J=2.6 Hz, 8.9 Hz, 1H), 7.15 (d, J=2.6 Hz, 1H),7.21 to 7.50 (m, 8H), 7.72 (d, J=8.9 Hz, 1H), 8.18 (d, J=8.9 Hz, 1H)

Example 556-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-4-nicotinoyloxy-2H-pyran-2-one

[0532]¹H NMR (δppm, CDCl₃): 2.04 (s, 3H), 2.33 (s, 3H), 5.12 (s, 2H),7.07 (dd, J=2.6 Hz, 8.9 Hz, 1H), 7.16 (d, J=2.6 Hz, 1H), 7.31 to 7.60(m, 8H), 8.48 (d, J=7.9 Hz, 1H), 8.94 (brs, 1H), 9.43 (s, 1H)

Example 566-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-4-isonicotinoyloxy-2H-pyran-2-one

[0533]¹H NMR (δppm, CDCl₃):2.03 (s, 3H), 2.32 (s, 3H), 5.12 (s, 2H),7.07 (dd, J=2.3 Hz, 8.9 Hz, 1H), 7.16 (d, J=2.3 Hz, 1H), 7.30 to 7.50(m, 7H), 8.03 (d, J=5.9 Hz, 2H), 8.94 (d, J=5.9 Hz, 2H)

Example 576-(5-benzyloxybenzofuran-2-yl)-5-ethyl-4-hydroxy-3-methyl-2H-pyran-2-one

[0534]¹H NMR (δppm, DMSO-d6): 1.17 (t, J=7.3 Hz, 3H), 1.93 (s, 3H), 2.78(q, J=7.3 Hz, 2H), 5.14 (s, 2H), 7.07 (dd, J=2.6 Hz, 8.9 Hz, 1H), 7.29to 7.48 (m, 7H), 7.57 (d, J=9.2 Hz, 1H), 10.87 (brs, 1H)

Example 58 5-ethyl-4-hydroxy-3-methyl-6-(5-(3-pyrimidinylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0535]¹H NMR (δppm, DMSO-d6): 1.24 (t, J=7.3 Hz, 3H), 1.99 (s, 3H) 2.93(q, J=7.3 Hz, 2H), 5.20 (s, 2H), 7.07 to 7.10 (m, 1H), 7.27 to 7.28 (m,2H), 7.45 to 7.49 (m, 2H), 7.97 (d, J=7.6 Hz, 1H), 8.51 (m, 1H), 8.67(s, 1H)

Example 594-acetyloxy-3,5-dimethyl-6-(5-(2-thiazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0536]¹H NMR (δppm, CDCl₃): 2.13 (s, 3H), 2.34 (s, 3H), 2.41 (s, 3H),5.30 (s, 2H), 7.09 (dd, J=8.6 Hz, 2,4 Hz, 1H), 7.32 (s, 1H), 7.36 (d,J=1.9 Hz, 1H), 7.47 (d, J=1.9 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.86 (d,J=2.4 Hz, 1H)

Example 604-hydroxy-3,5-dimethyl-6-(5-(2-thiazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0537]¹H NMR (δppm, CD3OD): 1.98 (s, 3H), 2.29 (s, 3H), 5.41 (s, 2H),6.87 (dd, J=8.9 Hz, 2.4 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 7.48 (d, J=8.9Hz, 1H), 7.87 (d, J=3.2 Hz, 1H), 7.91 (d, J=3.2 Hz, 1H), 9.40 (s, 1H)

Example 616-(benzofuran-2-yl)-3,5-dimethyl-4-(3-phenylpropionyloxy)-2H-pyran-2-one

[0538]¹H NMR (δppm, CDCl₃): 1.86 (s, 3H), 2.16 (s, 3H), 2.94 to 3.18 (m,4H), 7.20 to 7.41 (m, 8H), 7.52 (d, J=7.9 Hz, 1H), 7.64 (d, J=7.6 Hz,1H)

Example 626-(benzofuran-2-yl)-3,5-dimethyl-4-(2-furoyloxy)-2H-pyran-2-one

[0539]¹H NMR (δppm, CDCl₃): 2.04 (s, 3H), 2.35 (s, 3H), 6.67 (dd, J=1.7Hz, 3.6 Hz, 1H), 7.25 to 7.42 (m, 2H), 7.38 (s, 1H), 7.50 (d, J=3.6 Hz,1H), 7.53 (d, J=8.6 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.76 (d, J=1.7 Hz,1H)

Example 636-(benzofuran-2-yl)-3,5-dimethyl-4-nicotinoyloxy-2H-pyran-2-one

[0540]¹H NMR (δppm, CDCl₃): 2.05 (s, 3H), 2.36 (s, 3H), 7.26 to 7.43 (m,3H), 7.50 to 7.60 (m, 2H), 7.67 (d, J=7.6 Hz, 1H), 8.49 (d, J=7.9 Hz,1H), 8.95 (d, J=4.3 Hz, 1H), 9.44 (s, 1H)

Example 646-(benzofuran-2-yl)-3,5-dimethyl-4-(2-acetylamino-4-(morpholin-4-yl)-4-oxobutyryloxy)-2H-pyran-2-one

[0541]¹H NMR (δppm, CDCl₃): 2.01 (s, 3H), 2.05 (s, 3H), 2.33 (s, 3H),3.00 (dd, J=4.4 Hz, 16.8 Hz, 1H), 3.16 (dd, J=7.6 Hz, 16.8 Hz, 1H), 3.60to 3.73 (m, 8H), 5.37 to 5.44 (m, 1H), 6.44 (d, J=9.3 Hz, 1H), 7.27 to7.40 (m, 3H), 7.52 (d, J=8.3 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H)

Example 654-acetyloxy-6-(5-bromobenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one

[0542]¹H NMR (δppm, CDCl₃): 2.00 (s, 3H), 2.30 (s, 3H), 2.40 (s, 3H),7.29 (s, 1H), 7.40 (d, J=8.9 Hz, 1H), 7.47 (dd, J=8.9 Hz, 2.2 Hz, 1H),7.78 (d, J=2.2 Hz, 1H)

Example 666-(benzofuran-2-yl)-5-cyclopentylmethyl-4-hydroxy-3-methyl-2H-pyran-2-one

[0543]¹H NMR (δppm, DMSO-d6): 1.16 to 1.27 (m, 2H), 1.40 to 1.69 (m,6H), 1.94 (s, 3H), 2.02 to 2.17 (m, 1H), 2.90 (d, J=7.3 Hz, 2H), 7.29 to7.44 (m, 3H), 7.65 (d, J=8.2 Hz, 1H), 7.74 (d, J=7.3 Hz, 1H), 10.85 (s,1H)

Example 676-(benzofuran-2-yl)-4-hydroxy-3-methyl-5-phenoxy-2H-pyran-2-one

[0544]¹H NMR (δppm, DMSO-d6): 2.03 (s, 3H), 7.11 to 7.22 (m, 3H), 7.32to 7.49 (m, 5H), 7.69 (d, J=8.3 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 11.56(brs, 1H)

Example 686-(benzofuran-2-yl)-5-(2-butenyl)-4-hydroxy-3-methyl-2H-pyran-2-one

[0545]¹H NMR (δppm, DMSO-d6): 1.70 to 1.78 (m, 3H), 2.03 (s, 3H), 3.57to 3.64 (m, 2H), 5.61 to 5.67 (m, 2H), 7.39 to 7.54 (m, 3H), 7.78 (d,J=8.3 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 11.00 (brs, 1H)

Example 696-(benzofuran-2-yl)-4-(1-carbobenzyloxy-2-pyrrolidon-5-ylcarboxy)-3,5-dimethyl-2H-pyran-2-one

[0546]¹H NMR (δppm, CDCl₃): 1.94 (s, 3H), 2.25 (s, 3H), 2.30 to 2.40 (m,1H), 2.51 to 2.88 (m, 3H), 5.03 (dd, J=2.6 Hz, 8.9 Hz, 1H), 5.33, 5.38(ABq, J=2.2 Hz, 2H), 7.28 to 7.48 (m, 8H), 7.52 (d, J=8.6 Hz, 1H), 7.66(d, J=7.9 Hz, 1H)

Example 706-(benzofuran-2-yl)-3,5-dimethyl-4-(2-pyrrolidon-5-ylcarboxy)-2H-pyran-2-one

[0547]¹H NMR (δppm, DMSO-d6): 1.91 (s, 3H), 2.23 (s, 3H), 2.19 to 2.38(m, 3H), 2.47 to 2.66 (m, 1H), 4.65 to 4.73 (m, 1H), 7.31 to 7.40 (m,1H), 7.41 to 7.50 (m, 1H), 7.53 (s, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.77(d, J=7.6 Hz, 1H), 8.34 (s, 1H)

Example 71 6-(benzofuran-2-yl)-4-(2-(t-butoxycarbonylamino)acetyloxy)-3,5-dimethyl-2H-pyran-2-one

[0548]¹H NMR (δppm, CDCl₃): 1.48 (s, 9H), 2.00 (s, 3H), 2.32 (s, 3H),4.23 (d, J=6.3 Hz, 2H), 5.10 (brs, 1H), 7.25 to 7.42 (m, 3H), 7.53 (d,J=7.9 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H)

Example 726-(benzofuran-2-yl)-4-(2,4-dimethoxybenzoyloxy)-3,5-dimethyl-2H-pyran-2-one

[0549]¹H NMR (δppm, CDCl₃): 2.05 (s, 3H), 2.35 (s, 3H), 3.92 (s, 3H),3.95 (s, 3H), 6.54 to 6.66 (m, 2H), 7.25 to 7.41 (m, 3H), 7.52 (d, J=8.2Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H)

Example 736-(benzofuran-2-yl)-4-(2,6-dimethoxybenzoyloxy)-3,5-dimethyl-2H-pyran-2-one

[0550]¹H NMR (δppm, CDCl₃): 2.17 (s, 3H), 2.48 (s, 3H), 3.91 (s, 6H),6.65 (d, J=8.3 Hz, 2H), 7.25 to 7.45 (m, 4H), 7.54 (d, J=8.2 Hz, 1H),7.66 (d, J=7.9 Hz, 1H)

Example 746-(benzofuran-2-yl)-3,5-dimethyl-4-(6-hydroxynicotinoyloxy)-2H-pyran-2-one

[0551]¹H NMR (δppm, DMSO-d6): 1.91 (s, 3H), 2.24 (s, 3H), 6.48 (d, J=9.9Hz, 1H), 7.31 to 7.50 (m, 2H), 7.54 (s, 1H), 7.71 (d, J=8.3 Hz, 1H),7.78 (d, J=7.9 Hz, 1H), 7.95 (d, J=9.9 Hz, 1H), 8.43 (s, 1H), 12.51(brs, 1H)

Example 756-(benzofuran-2-yl)-3,5-dimethyl-4-(3-dimethylaminobenzoyloxy)-2H-pyran-2-one

[0552]¹H NMR (δppm, CDCl₃): 2.04 (s, 3H), 2.35 (s, 3H), 3.05 (s, 6H),7.04 (dd, J=2.6 Hz, 8.6 Hz, 1H), 7.25 to 7.44 (m, 4H), 7.48 to 7.59 (m,3H), 7.66 (d, J=7.6 Hz, 1H)

Example 764-(4-(acetylamino)benzoyloxy)-6-(benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one

[0553]¹H NMR (δppm, CDCl₃): 2.03 (s, 3H), 2.26 (s, 3H), 2.33 (s, 3H),7.24 to 7.41 (m, 3H), 7.49 (s, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.66 (d,J=7.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 8.18 (d, J=8.6 Hz, 2H)

Example 77 3,5-dimethyl-6-(6-(2-fluorobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0554] Mass analysis: [M⁺+H]=381.0

Example 783,5-dimethyl-6-(5-(2-fluorobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0555] Mass analysis: [M⁺+H]=381.0

Example 796-(5-(4-chlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0556] Mass analysis: [M⁺+H]=397.0

Example 806-(6-(2-bromobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0557] Mass analysis: [M⁺+H]=442.0

Example 816-(5-(2-bromobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0558] Mass analysis: [M⁺+H]=442.0

Example 826-(6-(3-bromobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0559] Mass analysis: [M⁺+H]=442.0

Example 836-(5-(3-bromobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0560] Mass analysis: [M⁺+H]=442.0

Example 84 3,5-dimethyl-4-hydroxy-6-(6-(3,4-(methylenedioxy)benzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0561] Mass analysis: [M⁺+H]=407.0

Example 85 3,5-dimethyl-4-hydroxy-6-(5-(3,4-(methylenedioxy)benzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0562] Mass analysis: [M⁺+H]=407.0

Example 86 3,5-dimethyl-4-hydroxy-6-(6-(2-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0563] Mass analysis: [M⁺+H]=364.0

Example 87 3,5-dimethyl-4-hydroxy-6-(5-(2-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0564] Mass analysis: [M⁺+H]=364.0

Example 88 3,5-dimethyl-4-hydroxy-6-(6-(3-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0565] Mass analysis: [M⁺+H]=364.0

Example 89 3,5-dimethyl-4-hydroxy-6-(5-(3-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0566] Mass analysis: [M⁺+H]=364.0

Example 90 3,5-dimethyl-4-hydroxy-6-(6-(4-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0567] Mass analysis: [M⁺+H]=364.0

Example 91 3,5-dimethyl-4-hydroxy-6-(5-(4-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0568] Mass analysis: [M⁺+H]=364.0

Example 923,5-dimethyl-4-hydroxy-6-(6-(tetrahydrofuran-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0569] Mass analysis: [M⁺+H]=357.0

Example 933,5-dimethyl-4-hydroxy-6-(5-(tetrahydrofuran-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0570] Mass analysis: [M⁺+H]=357.0

Example 943,5-dimethyl-4-hydroxy-6-(6-(1-methylpiperidin-2-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0571] Mass analysis: [M⁺+H]=384.0

Example 953,5-dimethyl-4-hydroxy-6-(5-(1-methylpiperidin-2-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0572] Mass analysis: [M⁺+H]=384.0

Example 963,5-dimethyl-4-hydroxy-6-(6-(1-methylpiperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0573] Mass analysis: [M⁺+H]=384.0

Example 973,5-dimethyl-4-hydroxy-6-(5-(1-methylpiperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0574] Mass analysis: [M⁺+H]=384.0

Example 98 3,5-dimethyl-4-hydroxy-6-(6-(1-methyl-3-piperidyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0575] Mass analysis: [M⁺+H]=370.0

Example 99 3,5-dimethyl-4-hydroxy-6-(5-(1-methyl-3-piperidyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0576] Mass analysis: [M⁺+H]=370.0

Example 100 3,5-dimethyl-4-hydroxy-6-(5-(1-methyl-3-pyrrolidyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0577] Mass analysis: [M⁺+H]=356.0

Example 101 3,5-dimethyl-4-hydroxy-6-(5-(1-methyl-3-pyrrolidyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0578] Mass analysis: [M⁺+H]=356.0

Example 102 3,5-dimethyl-4-hydroxy-6-(6-(2-pyrrolidinylethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0579] Mass analysis: [M⁺+H]=370.0

Example 103 3,5-dimethyl-4-hydroxy-6-(5-(2-pyrrolidinylethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0580] Mass analysis: [M⁺+H]=370.0

Example 1046-(6-(4-(diethylamino)-1-methylbutoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0581] Mass analysis: [M⁺+H]=414.0

Example 1056-(5-(4-(diethylamino)-1-methylbutoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0582] Mass analysis: [M⁺+H]=414.0

Example 1066-(6-(1,3-bis(dimethylamino)-2-propoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0583] Mass analysis: [M⁺+H]=401.0

Example 1076-(5-(1,3-bis(dimethylamino)-2-propoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0584] Mass analysis: [M⁺+H]=401.0

Example 1083,5-dimethyl-4-hydroxy-6-(6-(2-pyrrolidon-5-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0585] Mass analysis: [M⁺+H]=370.0

Example 1093,5-dimethyl-4-hydroxy-6-(5-(2-pyrrolidon-5-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0586] Mass analysis: [M⁺+H]=370.0

Example 1106-(6-(chroman-4-yloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0587] Mass analysis: [M⁺+H]=405.0

Example 1116-(5-(chroman-4-yloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0588] Mass analysis: [M⁺+H]=405.0

Example 1126-(6-(1-(n-butoxycarbonyl)ethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0589] Mass analysis: [M⁺+H]=401.0

Example 1136-(5-(1-(n-butoxycarbonyl)ethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0590] Mass analysis: [M⁺+H]=401.0

Example 1143,5-dimethyl-4-hydroxy-6-(6-(2-(morpholin-4-yl)ethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0591] Mass analysis: [M⁺+H]=386.0

Example 1153,5-dimethyl-4-hydroxy-6-(5-(2-(morpholin-4-yl)ethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0592] Mass analysis: [M⁺+H]=386.0

Example 1166-(6-(4-carboxybenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0593] Mass analysis: [M⁺+H]=407.0

Example 1176-(5-(4-carboxybenzyloxy)benzofuran-2-yl-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0594] Mass analysis: [M⁺+H]=407.0

Example 1186-(6-(4-chlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0595] Mass analysis: [M⁺+H]=397.0

Example 119 3,5-dimethyl-4-hydroxy-6-(6-(2-(trifluoromethyl)benzoyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0596] Mass analysis: [M⁺+H]=431.0

Example 120 3,5-dimethyl-4-hydroxy-6-(5-(2-(trifluoromethyl)benzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0597] Mass analysis: [M⁺+H]=431.0

Example 121 3,5-dimethyl-4-hydroxy-6-(6-(3-(trifluoromethyl)benzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0598] Mass analysis: [M⁺+H]=431.0

Example 122 3,5-dimethyl-4-hydroxy-6-(5-(3-(trifluoromethyl)benzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0599] Mass analysis: [M⁺+H]=431.0

Example 123 3,5-dimethyl-4-hydroxy-6-(6-(4-(trifluoromethyl)benzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0600] Mass analysis: [M⁺+H]=431.0

Example 124 3,5-dimethyl-4-hydroxy-6-(5-(4-(trifluoromethyl)benzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0601] Mass analysis: [M⁺+H]=431.0

Example 1256-(6-(cyclopentylmethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0602] Mass analysis: [M⁺+H]=355.0

Example 1266-(5-(cyclopentylmethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0603] Mass analysis: [M⁺+H]=355.0

Example 1276-(6-(cyclopropylmethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0604] Mass analysis: [M⁺+H]=327.0

Example 1286-(5-(cyclopropylmethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0605] Mass analysis: [M⁺+H]=327.0

Example 1296-(6-(2,4-dimethylbenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0606] Mass analysis: [M⁺+H]=391.0

Example 1306-(5-(2,4-dimethylbenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0607] Mass analysis: [M⁺+H]=391.0

Example 1316-(6-(2,5-dimethylbenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0608] Mass analysis: [M⁺+H]=391.0

Example 1326-(5-(2,5-dimethylbenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0609] Mass analysis: [M⁺+H]=391.0

Example 1336-(6-(3,4-dimethylbenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0610] Mass analysis: [M⁺+H]=391.0

Example 1346-(5-(3,4-dimethylbenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0611] Mass analysis: [M⁺+H]=391.0

Example 1356-(6-(3,5-dimethylbenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0612] Mass analysis: [M⁺+H]=391.0

Example 1366-(5-(3,5-dimethylbenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0613] Mass analysis: [M⁺+H]=391.0

Example 137 3,5-dimethyl-4-hydroxy-6-(6-((2-thienyl)methoxy)benzofuran-2-yl)-2H-pyran-2-one

[0614] Mass analysis: [M⁺+H]=369.0

Example 138 3,5-dimethyl-4-hydroxy-6-(5-((2-thienyl)methoxy)benzofuran-2-yl)-2H-pyran-2-one

[0615] Mass analysis: [M⁺+H]=369.0

Example 1393,5-dimethyl-6-(6-((2-furyl)methoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0616] Mass analysis: [M⁺+H]=353.0

Example 1403,5-dimethyl-6-(5-((2-furyl)methoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0617] Mass analysis: [M⁺+H]=353.0

Example 141 3,5-dimethyl-4-hydroxy-6-(6-(2-phenoxyethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0618] Mass analysis: [M⁺+H]=392.0

Example 142 3,5-dimethyl-4-hydroxy-6-(5-(2-phenoxyethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0619] Mass analysis: [M⁺+H]=392.0

Example 143 3,5-dimethyl-4-hydroxy-6-(6-(1-(2-(trifluoromethyl)phenyl)ethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0620] Mass analysis: [M⁺+H]=445.0

Example 144 3,5-dimethyl-4-hydroxy-6-(5-(1-(2-(trifluoromethyl)phenyl)ethoxy)benzofuran-2-yl-2H-pyran-2-one

[0621] Mass analysis: [M⁺+H]=445.0

Example 1456-(6-(2-chloro-5-nitrobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0622] Mass analysis: [M⁺+H]=442.0

Example 1466-(6-(3-chloro-6-nitrobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0623] Mass analysis: [M⁺+H]=442.0

Example 1476-(5-(3-chloro-6-nitrobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0624] Mass analysis: [M⁺+H]=442.0

Example 1486-(6-(2-cyclohexylethoxy)benzofuran-2-yl)-5-dimethyl-4-hydroxy-2H-pyran-2-one

[0625] Mass analysis: [M⁺+H]=383.0

Example 1496(5-(2-cyclohexylethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0626] Mass analysis: [M⁺+H]=383.0

Example 1503,5-dimethyl-4-hydroxy-6-(6-(1,4-pentadien-3-yloxy)benzofuran-2-yl)-2H-pyran-2-one

[0627] Mass analysis: [M⁺+H]=339.0

Example 1513,5-dimethyl-4-hydroxy-6-(5-(1,4-pentadien-3-yloxy)benzofuran-2-yl)-2H-pyran-2-one

[0628] Mass analysis: [M⁺+H]=339.0

Example 1526-(6-(2,4-dichlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0629] Mass analysis: [M⁺+H]=432.0

Example 1536-(5-(2,4-dichlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0630] Mass analysis: [M⁺+H]=432.0

Example 1546-(6-(2,5-dichlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0631] Mass analysis: [M⁺+H]=432.0

Example 1556-(5-(2,5-dichlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0632] Mass analysis: [M⁺+H]=432.0

Example 1566-(6-(2,6-dichlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0633] Mass analysis: [M⁺+H]=432.0

Example 1576-(5-(2,6-dichlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0634] Mass analysis: [M⁺+H]=432.0

Example 1586-(6-(3,4-dichlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0635] Mass analysis: [M⁺+H]=432.0

Example 1596-(5-(3,4-dichlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0636] Mass analysis: [M⁺+H]=432.0

Example 1606-(6-(3,5-dichlorbenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0637] Mass analysis: [M⁺+H]=432.0

Example 1616-(5-(3,5-dichlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0638] Mass analysis: [M⁺+H]=432.0

Example 1626-(6-(4-n-butoxybenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0639] Mass analysis: [M⁺+H]=435.0

Example 1636-(5-(4-n-butoxybenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0640] Mass analysis: [M⁺+H]=435.0

Example 1643,5-dimethyl-4-hydroxy-6-(6-(3-methyl-2-nitrobenzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0641] Mass analysis: [M⁺+H]=422.0

Example 1653,5-dimethyl-4-hydroxy-6-(5-(3-methyl-2-nitrobenzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0642] Mass analysis: [M⁺+H]=422.0

Example 166 3,5-dimethyl-6-(6-(2,3-dimethyl-4-methoxybenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0643] Mass analysis: [M⁺+H]=421.0

Example 167 3,5-dimethyl-6-(5-(2,3-dimethyl-4-methoxybenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0644] Mass analysis: [M⁺+H]=421.0

Example 1683,5-dimethyl-6-(6-(3,5-dinitrobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0645] Mass analysis: [M⁺+H]=453.0

Example 1693,5-dimethyl-6-(5-(3,5-dinitrobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0646] Mass analysis: [M⁺+H]=453.0

Example 170 3,5-dimethyl-4-hydroxy-6-(6-(1,2,3,4-tetrahydronaphthalen-1-yloxy)benzofuran-2-yl)-2H-pyran-2-one

[0647] Mass analysis: [M⁺+H]=403.0

Example 171 3,5-dimethyl-4-hydroxy-6-(5-(1,2,3,4-tetrahydronaphthalen-1-yloxy)benzofuran-2-yl)-2H-pyran-2-one

[0648] Mass analysis: [M⁺+H]=403.0

Example 172 3,5-dimethyl-4-hydroxy-6-(6-(1-naphthylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0649] Mass analysis: [M⁺+H]=413.0

Example 173 3,5-dimethyl-4-hydroxy-6-(5-(1-naphthylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0650] Mass analysis: [M⁺+H]=413.0

Example 174 3,5-dimethyl-4-hydroxy-6-(6-(2-naphthylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0651] Mass analysis: [M⁺+H]=413.0

Example 175 3,5-dimethyl-4-hydroxy-6-(5-(2-naphthylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0652] Mass analysis: [M⁺+H]=413.0

Example 1766-(6-(1,4-benzodioxan-2-ylmethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0653] Mass analysis: [M⁺+H]=421.0

Example 1776-(5-(1,4-benzodioxan-2-ylmethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0654] Mass analysis: [M⁺+H]=421.0

Example 1783,5-dimethyl-6-(6-(3-hexen-1-yloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0655] Mass analysis: [M⁺+H]=355.0

Example 1793,5-dimethyl-6-(5-(3-hexen-1-yloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0656] Mass analysis: [M⁺+H]=355.0

Example 1806-(6-(2-butyn-1-yloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0657] Mass analysis: [M⁺+H]=325.0

Example 1816-(5-(2-butyn-1-yloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0658] Mass analysis: [M⁺+H]=325.0

Example 1823,5-dimethyl-6-(6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0659] Mass analysis: [M⁺+H]=387.0

Example 1833,5-dimethyl-6-(5-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0660] Mass analysis: [M⁺+H]=387.0

Example 1843,5-dimethyl-6-(6-(2-ethoxyethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0661] Mass analysis: [M⁺+H]=345.0

Example 1853,5-dimethyl-6-(5-(2-ethoxyethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0662] Mass analysis: [M⁺+H]=345.0

Example 1863,5-dimethyl-4-hydroxy-6-(6-(3-methyloxetan-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0663] Mass analysis: [M⁺+H]=357.0

Example 1873,5-dimethyl-4-hydroxy-6-(5-(3-methyloxetan-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0664] Mass analysis: [M⁺+H]=357.0

Example 1883,5-dimethyl-6-(6-(5-hexyn-1-yloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0665] Mass analysis: [M⁺+H]=353.0

Example 1893,5-dimethyl-6-(5-(5-hexyn-1-yloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0666] Mass analysis: [M⁺+H]=353.0

Example 1903,5-dimethyl-6-(6-(5-hexen-1-yloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0667] Mass analysis: [M⁺+H]=355.0

Example 1913,5-dimethyl-6-(5-(5-hexen-1-yloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0668] Mass analysis: [M⁺+H]=355.0

Example 1923,5-dimethyl-6-(6-(2,2-dimethylpropoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0669] Mass analysis: [M⁺+H]=343.0

Example 1933,5-dimethyl-6-(5-(2,2-dimethylpropoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0670] Mass analysis: [M⁺+H]=343.0

Example 1943,5-dimethyl-6-(6-(2,2-diphenylethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0671] Mass analysis: [M⁺+H]=453.0

Example 1953,5-dimethyl-6-(5-(2,2-diphenylethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0672] Mass analysis: [M⁺+H]=453.0

Example 196 3,5-dimethyl-4-hydroxy-6-(6-(2-phenyl-2-propoxy)benzofuran-2-yl)-2H-pyran-2-one

[0673] Mass analysis: [M⁺+H]=391.0

Example 197 3,5-dimethyl-4-hydroxy-6-(5-(2-phenyl-2-propoxy)benzofuran-2-yl)-2H-pyran-2-one

[0674] Mass analysis: [M⁺+H]=391.0

Example 198 3,5-dimethyl-4-hydroxy-6-(6-(2-(1-naphthyl)ethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0675] Mass analysis: [M⁺+H]=427.0

Example 199 3,5-dimethyl-4-hydroxy-6-(5-(2-(1-naphthyl)ethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0676] Mass analysis: [M⁺+H]=427.0

Example 2006-(6-(bis(4-methoxyphenyl)methoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0677] Mass analysis: [M⁺+H]=499.0

Example 2016-(5-(bis(4-methoxyphenyl)methoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0678] Mass analysis: [M⁺+H]=499.0

Example 202 3,5-dimethyl-4-hydroxy-6-(6-(3-phenylpropoxy)benzofuran-2-yl)-2H-pyran-2-one

[0679] Mass analysis: [M⁺+H]=391.0

Example 203 3,5-dimethyl-4-hydroxy-6-(5-(3-phenylpropoxy)benzofuran-2-yl)-2H-pyran-2-one

[0680] Mass analysis: [M⁺+H]=391.0

Example 204 3,5-dimethyl-4-hydroxy-6-(6-(4-phenylbutoxy)benzofuran-2-yl)-2H-pyran-2-one

[0681] Mass analysis: [M⁺+H]=405.0

Example 205 3,5-dimethyl-4-hydroxy-6-(5-(4-phenylbutoxy)benzofuran-2-yl)-2H-pyran-2-one

[0682] Mass analysis: [M⁺+H]=405.0

Example 2066-(6-(cyclohexylmethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0683] Mass analysis: [M⁺+H]=369.0

Example 2076-(5-(cyclohexylmethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0684] Mass analysis: [M⁺+H]=369.0

Example 2086-(6-(3-cyclohexylpropoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0685] Mass analysis: [M⁺+H]=397.0

Example 2096-(5-(3-cyclohexylpropoxy)benzofuran-2-yl)-5-dimethyl-4-hydroxy-2H-pyran-2-one

[0686] Mass analysis: [M⁺+H]=397.0

Example 2106-(6-(3-buten-1-yloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0687] Mass analysis: [M⁺+H]=327.0

Example 2116-(5-(3-buten-1-yloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0688] Mass analysis: [M⁺+H]=327.0

Example 2126-(6-(2-(benzyloxy)ethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0689] Mass analysis: [M⁺+H]=407.0

Example 2136-(5-(2-(benzyloxy)ethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0690] Mass analysis: [M⁺+H]=407.0

Example 2143,5-dimethyl-4-hydroxy-6-(6-(2-propyn-1-yloxy)benzofuran-2-yl)-2H-pyran-2-one

[0691] Mass analysis: [M⁺+H]=311.0

Example 2153,5-dimethyl-4-hydroxy-6-(5-(2-propyn-1-yloxy)benzofuran-2-yl)-2H-pyran-2-one

[0692] Mass analysis: [M⁺+H]=311.0

Example 216 3,5-dimethyl-6-(6-(5-(ethoxycarbonyl) pentyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0693] Mass analysis: [M⁺+H]=415.0

Example 217 3,5-dimethyl-6-(5-(5-(ethoxycarbonyl)pentyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0694] Mass analysis: [M⁺+H]=415.0

Example 2183,5-dimethyl-6-(6-ethoxybenzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0695] Mass analysis: [M⁺+H]=301.0

Example 2193,5-dimethyl-4-hydroxy-6-(6-isopropoxybenzofuran-2-yl)-2H-pyran-2-one

[0696] Mass analysis: [M⁺+H]=329.0

Example 220 6-(5-(1-t-butoxycarbonylpiperidin-2-ylmethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0697] Mass analysis: [M⁺+H]=470.0

Example 221 6-(5-(1-t-butoxycarbonylpiperidin-4-ylmethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0698] Mass analysis: [M⁺+H]=470.0

Example 222 6-(5-(1-t-butoxycarbonylpiperidin-4-yloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0699] Mass analysis: [M⁺+H]=456.0

Example 223 6-(5-(1-t-butoxycarbonylpyrrolidin-3-yloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0700] Mass analysis: [M⁺+H]=442.0

Example 2246-(5-(4-(t-butoxycarbonylamino)butoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0701] Mass analysis: [M⁺+H]=444.0

Example 225 3,5-dimethyl-6-(6-(3-fluorobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0702] Mass analysis: [M⁺+H]=381.0

Example 2263,5-dimethyl-6-(5-(3-fluorobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0703] Mass analysis: [M⁺+H]=381.0

Example 2273,5-dimethyl-6-(6-(4-fluorobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0704] Mass analysis: [M⁺+H]=381.0

Example 2283,5-dimethyl-6-(5-(4-fluorobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one

[0705] Mass analysis: [M⁺+H]=381.0

Example 229 3,5-dimethyl-4-hydroxy-6-(6-(2-nitrobenzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0706] Mass analysis: [M⁺+H]=408.0

Example 230 3,5-dimethyl-4-hydroxy-6-(5-(2-nitrobenzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0707] Mass analysis: [M⁺+H]=408.0

Example 231 3,5-dimethyl-4-hydroxy-6-(6-(3-nitrobenzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0708] Mass analysis: [M⁺+H]=408.0

Example 232 3,5-dimethyl-4-hydroxy-6-(5-(3-nitrobenzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0709] Mass analysis: [M⁺+H]=408.0

Example 233 3,5-dimethyl-4-hydroxy-6-(6-(4-nitrobenzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0710] Mass analysis: [M⁺+H]=408.0

Example 234 3,5-dimethyl-4-hydroxy-6-(5-(4-nitrobenzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0711] Mass analysis: [M⁺+H]=408.0

Example 235 3,5-dimethyl-4-hydroxy-6-(6-(3-methoxybenzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0712] Mass analysis: [M⁺+H]=393.0

Example 236 3,5-dimethyl-4-hydroxy-6-(5-(3-methoxybenzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0713] Mass analysis: [M⁺+H]=393.0

Example 237 3,5-dimethyl-4-hydroxy-6-(6-(4-methoxybenzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0714] Mass analysis: [M⁺+H]=393.0

Example 238 3,5-dimethyl-4-hydroxy-6-(5-(4-methoxybenzyloxy)benzofuran-2-yl)-2H-pyran-2-one

[0715] Mass analysis: [M⁺+H]=393.0

Example 239 6-(6-(2-chlorobenzyloxy)benzofuran-2-yl)3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0716] Mass analysis: [M⁺+H]=397.0

Example 2406-(5-(2-chlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0717] Mass analysis: [M⁺+H]=397.0

Example 2416-6-(6-(3-chlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0718] Mass analysis: [M⁺+H]=397.0

Example 2426-(5-(3-chlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0719] Mass analysis: [M⁺+H]=397.0

Example 243 3,5-dimethyl-4-hydroxy-6-(5-(5-thiazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0720]¹H NMR (δppm, DMSO-d6): 1.93 (s, 3H), 2.28 (s, 3H), 5.44 (s, 2H),7.08 (dd, J=8.9 Hz, 2.7 Hz, 1H), 7.31 (s, 1H), 7.37 (d, J=2.7 Hz, 1H),7.59 (d, J=8.9 Hz, 1H), 8.02 (s, 1H), 9.11 (s, 1H)

Example 244 4-acetyloxy-6-(5-(2,4-dichloro-5-thiazolylmethoxy)benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one

[0721]¹H NMR (δppm, CDCl₃): 2.00 (s, 3H), 2.30 (s, 3H), 2.39 (s, 3H),5.21 (s, 2H), 7.01 (dd, J=8.9 Hz, 2.4 Hz, 1H), 7.04 (d, J=8.9 Hz, 1H),7.27 (d, J=2.4 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H)

Example 2453,5-dimethyl-4-hydroxy-6-(5-(2-(morpholinesulfonyl)-5-thiazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0722]¹H NMR (δppm, DMSO-d6): 1.94 (s, 3H), 2.29 (s, 3H), 3.15-3.18 (m,4H), 3.64 to 3.67 (m, 4H), 5.53 (s, 2H), 7.12 (dd, J=8.8 Hz, 2.7 Hz,1H), 7.34 (s, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 8.26(s, 1H)

Example 246 3,5-dimethyl-4-hydroxy-6-(5-(3-thienylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0723]¹H NMR (δppm, CD3OD): 1.93 (s, 3H), 2.33 (s, 3H), 5.13 (s, 2H),7.02 (dd, J=8.9 Hz, 2.7 Hz, 1H), 7.18 (d, J=2.7 Hz, 1H), 7.20 (s, 1H),7.24 (d, J=2.7 Hz, 1H), 7.39 to 7.45 (m, 3H)

Example 2473,5-dimethyl-4-hydroxy-6-(5-(2-(morpholinesulfonyl)-5-thienylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0724]¹H NMR (δppm, CDCl₃): 1.91 (s, 3H), 2.31 (s, 3H), 2.98 to 3.03 (m,4H), 3.71 to 3.75 (m, 4H), 5.38 (s, 2H), 7.03 (dd, J=8.9 Hz, 2.7 Hz,1H), 7.19 (s, 1H), 7.27 to 7.29 (m, 2H), 7.51 (d, J=2.7 Hz, 1H)

Example 248 4-acetyloxy-3,5-dimethyl-6-(5-(2-(morpholinesulfonyl)-5-thienylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0725]¹H NMR (δppm, CDCl₃): 2.00 (s, 3H), 2.30 (s, 3H), 2.40 (s, 3H),3.06 to 3.10 (m, 4H), 3.74 to 3.81 (m, 4H), 5.29 (s, 2H), 7.04 (dd,J=9.2 Hz, 2.7 Hz, 1H), 7.15 (d, J=2.7 Hz, 1H), 7.31 (s, 1H), 7.43 to7.47 (m, 2H)

Example 249 3,5-dimethyl-4-hydroxy-6-(5-(4-oxazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one

[0726] Mass analysis: [M⁺+H]=354.0

Example 2506-(5-(N-benzoyl-N-methylamino)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0727] Mass analysis: [M⁺+H]=390.0

Example 2513,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(phenylacetyl)amino)benzofuran-2-yl)-2H-pyran-2-one

[0728] Mass analysis: [M⁺+H]=404.5

Example 2523,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(2-thienylcarhonyl)amino)benzofuran-2-yl)-2H-pyran-2-one

[0729] Mass analysis: [M⁺+H]=396.0

Example 2533,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(3-pyridylcarbonyl)amino)benzofuran-2-yl)-2H-pyran-2-one

[0730] Mass analysis: [M⁺+H]=391.0

Example 2543,5-dimethyl-4-hydroxy-6-(5-(N-isobutyryl-N-methylamino)benzofuran-2-yl)-2H-pyran-2-one

[0731] Mass analysis: [M⁺+H]=356.0

Example 255 6-(5-(N-(t-butoxycarbonyl)-N-methylamino)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

[0732] Mass analysis: [M⁺+H]=386.0

[0733] The following compounds were also produced by processes similarto those described in the preceding examples and production examples,using organic chemical techniques well-known to those skilled in theart.

Example 2566-(5-benzoylaminobenzofuran-2-yl)-4-benzoyloxy-3,5-dimethyl-2H-pyran-2-oneExample 257 4-acetyloxy-3,5-dimethyl-6-(5-trifluoromethanesulfonyloxybenzofuran-2-yl)-2H-pyran-2-one Example 2586-(4-benzyloxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-oneExample 259 4-acetyloxy-3,5-dimethyl-6-(5-(methoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one Example 2604-acetyloxy-6-(4-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-oneExample 2614-acetyloxy-3,5-dimethyl-6-(5-hydroxybenzofuran-2-yl)-2H-pyran-2-oneExample 2623,5-dimethyl-4-hydroxy-6-(5-hydroxybenzofuran-2-yl)-2H-pyran-2-oneExample 263 4-acetyloxy-3,5-dimethyl-6-(5-(4-methoxybenzoyloxy)benzofuran-2-yl)-2H-pyran-2-one Example 2644-acetyloxy-6-(5-carboxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-oneExample 2654-acetyloxy-6-(4-acetyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-oneExample 2664-acetyloxy-3,5-dimethyl-6-(4-methoxybenzofuran-2-yl)-2H-pyran-2-oneExample 2673,5-dimethyl-4-hydroxy-6-(4-methoxybenzofuran-2-yl)-2H-pyran-2-oneExample 2684-acetyloxy-3,5-dimethyl-6-(5-methoxybenzofuran-2-yl)-2H-pyran-2-oneExample 2694-acetyloxy-6-(5-acetyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-oneExample 2704-acetyloxy-6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-oneExample 2716-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-oneExample 2723,5-dimethyl-4-hydroxy-6-(6-hydroxybenzofuran-2-yl)-2H-pyran-2-oneExample 2734-acetyloxy-3,5-dimethyl-6-(6-methoxybenzofuran-2-yl)-2H-pyran-2-oneExample 274 4-acetyloxy-3,5-dimethyl-6-(5-p-toluenesulfonyloxybenzofuran-2-yl)-2H-pyran-2-one Example 2754-acetyloxy-6-(6-acetyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-oneExample 2766-(6-cyclohexylozybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-oneExample 277 3,5-dimethyl-4-hydroxy-6-(6-trifluoromethanesulfonyloxybenzofuran-2-yl)-2H-pyran-2-one Example 2784-acetyloxy-3,5-dimethyl-6-(6-(2-(methoxycarbonyl)ethoxy)benzofuran-2-yl)-2H-pyran-2-one Example 2793,5-dimethyl-4-hydroxy-6-(6-(2-(methoxycarbonyl)ethoxy)benzofuran-2-yl)-2H-pyran-2-one Example 2804-acetyloxy-6-(6-(2-(acetyloxy)ethoxy)benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-oneExample 2813,5-dimethyl-4-hydroxy-6-(7-hydroxybenzofuran-2-yl)-2H-pyran-2-oneExample 2824-acetyloxy-3,5-dimethyl-6-(7-methoxybenzofuran-2-yl)-2H-pyran-2-oneExample 2833,5-dimethyl-4-hydroxy-6-(4-hydroxybenzofuran-2-yl)-2H-pyran-2-oneExample 2844-acetyloxy-6-(7-acetyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-oneExample 285 4-acetyloxy-6-(7-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one Example 2866-(7-benzyloxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-oneExample 2874-acetyloxy-6-(benzofuran-2-yl)-3-isopropyl-5-methyl-2H-pyran-2-oneExample 2886-(4,6-dimethoxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-oneExample 2894-acetyloxy-6-(4,6-dimethoxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-oneExample 290 3,5-dimethyl-4-hydroxy-6-(5-(methoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one Example 2913,5-dimethyl-4-hydroxy-6-(6-methoxymethoxybenzofuran-2-yl)-2H-pyran-2-one Example 2924-acetyloxy-3,5-dimethyl-6-(6-methoxymethoxybenzofuran-2-yl)-2H-pyran-2-one Example 2936-(5-carboxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-oneExample 294 4-acetyloxy-3,5-dimethyl-6-(5-(phenoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one Example 2954-acetyloxy-3,5-dimethyl-6-(5-(phenylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-one Example 2964-acetyloxy-6-(5-benzoyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-oneExample 297 6-(5-(N-(4-chlorophenylsulfonyl)-N-methylamino)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one Example 2983,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-phenylsulfonyl)benzofuran-2-yl)-2H-pyran-2-oneExample 2993,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-phenylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-oneExample 3006-(5-(benzimidazolylcarbamoyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-oneExample 3016-(5-(benzothiazolylcarbamoyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-oneExample 302 3,5-dimethyl-4-hydroxy-6-(5-(1,3,4-trihydroisoquinolin-2-ylcarbonyl)benzofuran-2-yl)-2H-pyran-2-one Example 3033,5-dimethyl-4-hydroxy-6-(5-morpholinylbenzofuran-2-yl)-2H-pyran-2-oneExample 3043,5-dimethyl-4-hydroxy-6-(5-(5-hydroxy-3-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-oneExample 305 3,5-dimethyl-4-hydroxy-6-(5-(4-(sulfamoyl)phenylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-one Example 3063,5-dimethyl-4-hydroxy-6-(5-(4-pyridylmethylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-one Example 3073,5-dimethyl-4-hydroxy-6-(5-(4-piperidinyl)benzofuran-2-yl)-2H-pyran-2-one Example 3086-(5-(N-benzyl-N-methylcarbamoyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-oneExample 309 3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(4-pyridyl)carbamoyl)benzofuran-2-yl)-2H-pyran-2-one Example 310

[0734] Preparation of Cells

[0735] Human hepatic cancer cells HepG2 were inoculated into a 24-wellplate (Costar No. 3524) at 4×10⁴ cells/well, and 1 ml of medium (eRDFmedium containing 10% bovine serum (Kyokuto Chemical Co.)) was used for6 day culturing with 5% CO₂ at 37° C. After drawing off the supernatantmedium, the cells were freshly rinsed with 1 ml of PBS(−) buffersolution (Takara Shuzo) and drawn off. This procedure was repeated twiceand then 1 ml of fresh medium (eRDF medium) was added.

[0736] Preparation of Sample

[0737] 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one(Example 2) was dissolved in dimethylsulfoxide (DMSO) to prepare a 20 mMsample stock solution. A diluted solution was obtained by diluting thesample solution with DMSO.

[0738] TG Production

[0739] To the cells prepared above there were added the sample stocksolution or its diluted solution at 5 μl per well and 10 μl of¹⁴C-acetic acid solution (a solution of Amersham Code No. CFA13 diluted4.4-fold with PBS(−) buffer), and culturing was carried out for one daywith 5% CO₂ at 37° C.

[0740] TG Quantification

[0741] After the culturing was completed, the culture solution wasremoved, and 1 ml of extraction solution (a mixture of n-hexane andisopropyl alcohol at 2:1) was added for extraction treatment on thelipid components in the cells. After the treatment, the extractcontaining the obtained lipid components was air-dried, the residue wasredissolved in 20 μl of a mixed solution of n-hexane and ethyl acetateat 9:1, and the solution was spotted on a thin-layer chromatographyplate (S319, Tokyo Kasei) and developed by thin-layer chromatographywith the mixed solution mentioned above. After air-drying, the lipidcomponents were colored with iodine vapor, the portion corresponding toTG was cut out, and the amount of TG biosynthesized was measured with aliquid scintillation counter. The results are shown in Table 1. It wasdemonstrated that6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one exhibitstriglyceride biosynthesis inhibiting activity. TABLE 1 Sampleconcentration TG production (Example 2) inhibiting activity 1 μM 22% 10μM 70% 100 μM 98%

Example 311

[0742] The TG production inhibiting activity of the invention compoundswas evaluated in the same manner as the above example. According to theresults of the evaluation, the compounds of the following examplenumbers exhibited an IC₅₀ value of less than 10 μM, at least 30% TGproduction inhibiting activity at a concentration of 1 μM, or at least50% TG production inhibiting activity at a concentration of 10 μM: 1, 2,3, 4, 5, 9, 10, 11, 12, 13, 19, 25, 26, 27, 28, 29, 30, 31, 33, 34, 36,39, 40, 42, 45, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62,63, 64, 65, 66, 69, 70, 71, 72, 75, 76, 78, 85, 89, 97, 117, 120, 122,134, 138, 153, 159, 163, 170, 215, 226, 228, 236, 242, 243, 244, 245,246, 247, 248, 249, 250, 251, 252, 255, 257, 259, 260, 265, 268, 270,271, 274, 285, 290, 291, 297, 298, 299, 300, 301, 302, 303, 304, 305,306, 307, 308, 309.

[0743] The compounds of the following example numbers exhibited an IC₅₀value of at least 10 μM and less than 100 μM; at least 5% and less than30% TG production inhibiting activity at a concentration of 1 μM; or atleast 30% and less than 50% TG production inhibiting activity at aconcentration of 10 μM: 6, 7, 8, 14, 17, 18, 20, 22, 23, 24, 32, 35, 37,38, 43, 46, 47, 60, 67, 68, 74, 79, 81, 83, 87, 95, 107, 115, 124, 126,144, 155, 157, 175, 177, 179, 181, 183, 185, 187, 191, 193, 195, 197,201, 203, 207, 213, 217, 220, 222, 224, 230, 240, 253, 254, 258, 261,262, 263, 264, 266, 267, 269, 272, 273, 275, 278, 280, 281, 282, 283,284, 286, 287, 292, 295, 296.

Example 312 Drug Effect Evaluation Test

[0744] 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one(Example 2) was suspended in a 0.5% carboxymethyl cellulose Na aqueoussolution (vehicle) to prepare 20 mg/ml and 60 mg/ml administrationsolutions, and these were orally administered to 6-week-old SD male ratsat a dose of 5 ml/kg once a day, for 7 consecutive days. CE-2 by NihonCrea Co. was used for the rat feed, and the rats were allowed freeaccess to food and water. The rats were separated into avehicle-administered group of 6 rats and a drug-administered group of 6rats for a test. At 4 hours after the final drug administration, therats were killed under ether anesthesia, blood was drawn from theabdominal aorta, and the serum levels of TG, total cholesterol (TC) andHDL were measured.

[0745] Triglyceride EII-HA Test Wako (product of Wako Junyaku Kogyo) wasused for the TG measurement, HA Test Wako/Cholesterol E-HA Test Wako(product of Wako Junyaku Kogyo) was used for the total cholesterol (TC)measurement, and HDL-cholesterol Test Wako (product of Wako JunyakuKogyo) was used for the HDL measurement.

[0746] As shown in Table 2, the invention compound-administered grouphad dose-dependent lower TG levels. Also, as shown in Table 3, the TCand HDL levels increased in a dose dependent manner. The increase in TCwas almost totally due to an increase in HDL. No cases of rat death orinhibited body weight gain were found during the administration period.TABLE 2 Serum TG (mg/dl) Administered solution (mean ± SE) No sampleadministered  108 ± 8.9 Example 2 (100 mg/kg) 94.8 ± 6.5 Example 2 (300mg/kg) 74.8 ± 10.7

[0747] TABLE 3 Serum HDL-C (mg/dl) Administered solution (mean ± SE) Nosample administered 30.5 ± 1.7 Example 2 (100 mg/kg) 35.0 ± 3.1 Example2 (300 mg/kg) 42.2 ± 3.8

[0748] The above data demonstrate that the compounds of the inventionhave TG-lowering effects and/or HDL-elevating effects, and are thereforeuseful as blood triglyceride lowering agents, lipid metabolismenhancers, arteriosclerosis prophylactic agents or arteriosclerosistreatment agents.

Example 313

[0749] Tablets were prepared with each tablet having the followingcomposition. Active ingredient 200 μg Lactose 180 mg Potato starch  50mg Polyvinyl pyrrolidone  10 mg Magnesium stearate  5 mg

[0750] The active ingredient, lactose and potato starch were combined,and the mixture was evenly moistened with a 20% ethanol solution ofpolyvinyl pyrrolidone. The moistened mixture was passed through a 20mesh sieve, dried at 45° C. and then passed through a 15 mesh sieve. Thegranules obtained in this manner were blended with magnesium stearateand compressed into tablets.

Example 314

[0751] Hard gelatin capsules were prepared with each capsule containingthe following composition. Active ingredient 100 μg Fine crystallinecellulose 195 mg Amorphous silicic acid  5 mg

[0752] The active ingredient, fine crystalline cellulose and unpressedamorphous silicic acid were thoroughly blended and filled into hardgelatin capsules.

Example 315

[0753] The active ingredient was dissolved in fractionated coconut oil.This was heated and dissolved in a coating component having thefollowing formula, and a soft capsule manufacturing machine was used toprepare soft capsules by a common procedure, with 100 μg of the activeingredient in each capsule.

[0754] Coating Formula Gelatin   10 parts by weight Glycerin   5 partsby weight Sorbic acid 0.08 parts by weight Purified water   14 parts byweight

INDUSTRIAL APPLICABILITY

[0755] The pharmaceutical agents of the present invention exhibittriglyceride biosynthesis inhibiting action, blood triglyceride loweringeffects or blood HDL level elevating effects, and they may therefore beused as therapeutic agents for hypertriglyceridemia, as lipid metabolismenhancers, or as prophylactic and/or therapeutic agents forarteriosclerosis.

1. A benzofuryl-α-pyrone derivative represented by the followingstructural formula (I)

wherein R¹ represents hydrogen or an alkyl group of 1 to 5 carbons; R²represents hydrogen, —CO—R⁵ (wherein R⁵ represents hydrogen, an alkylgroup of 1 to 5 carbons with optional substituents, a cycloalkyl groupof 3 to 7 carbons, an aryl group of 6 to 10 carbons or a heterocycle),or —SO₂R⁶ (wherein R⁶ represents an optionally halogen-substituted alkylgroup of 1 to 5 carbons or aryl group of 6 to 10 carbons); R³ representshydrogen, an alkyl group of 1 to 5 carbons, an alkenyl group of 2 to 5carbons, an alkynyl group of 2 to 5 carbons, a cycloalkyl group of 3 to7 carbons, a cycloalkyl group of 3 to 7 carbons-alkyl group of 1 to 5carbons, an aryl group of 6 to 10 carbons, an aralkyl group of 7 to 20carbons, an alkoxy group of 1 to 5 carbons or an aryloxy group of 6 to10 carbons; R⁴ is a substituent at the c-4 position, c-5 position, c-6position or c-7 position of the benzofuran ring and represents: R^(4a)which represents hydrogen, a nitro group, a cyano group, a halogen atom,a heterocycle, an alkenyl group of 2 to 5 carbons, an alkynyl group of 2to 5 carbons, an aryl group of 6 to 10 carbons, A=CH(CH₂)_(n)— (whereinA represents an alicyclic heterocycle, “═” represents a double bond andn represents 0, 1 or 2), A=CH(CH₂)_(m)O— (wherein A represents analicyclic heterocycle, “═” represents a double bond and m represents 1,2 or 3), A-SO₂—(CH₂)_(m)— (wherein A represents an alicyclic heterocycleand m represents 1, 2 or 3), —OR⁷ (wherein R⁷ represents hydrogen, acycloalkyl group of 3 to 7 carbons, an aryl group of 6 to 10 carbons, aheterocycle or an optionally halogen-substituted alkylsulfonyl group of1 to 4 carbons or arylsulfonyl group of 6 to 10 carbons), —O—CO—R⁸(wherein R⁸ represents hydrogen, an alkyl group of 1 to 4 carbons, anaryl group of 6 to 10 carbons, an aralkyl group of 7 to 20 carbons or aheterocycle), —NR⁹R¹⁰ (wherein R⁹ and R¹⁰ each independently representshydrogen, an alkyl group of 1 to 4 carbons, an aralkyl group of 7 to 20carbons, a heterocycle, a phenyl group, —SO₂—R¹¹ (wherein R¹¹ representsan optionally halogen-substituted alkyl group of 1 to 12 carbons, aheterocycle-substituted alkyl group of 1 to 6 carbons, an aryl group of6 to 10 carbons, a heterocycle or an aralkyl group of 7 to 20 carbons)or —CO—R¹² (wherein R¹² represents hydrogen, an alkyl group of 1 to 12carbons, an aryl group of 6 to 10 carbons, an aralkyl group of 7 to 20carbons, a heterocycle, an alkoxy group of 1 to 10 carbons, aheterocycle-substituted alkyl group of 1 to 6 carbons, an aryloxy groupof 6 to 10 carbons, a heteroaryloxy group or an aralkyloxy group of 7 to20 carbons)), —CO—R¹³ (wherein R¹³ represents hydrogen, —OH, an alkylgroup of 1 to 4 carbons, an aryl group of 6 to 10 carbons, aheterocycle, an alkoxy group of 1 to 4 carbons, an aryloxy group of 6 to10 carbons or an aralkyloxy group of 7 to 20 carbons) or —CO—NR¹⁴R¹⁵(wherein R¹⁴ and R¹⁵ each independently represents hydrogen, an alkylgroup of 1 to 4 carbons, a cycloalkyl group of 3 to 7 carbons, an arylgroup of 6 to 10 carbons, an aralkyl group of 7 to 20 carbons, aheterocycle or a heterocycle-substituted alkyl group of 1 to 4 carbons);R^(4b) which represents a saturated or unsaturated alkoxy group of 1 to6 carbons optionally substituted with 1 to 3 groups selected from thegroup consisting of halogens, cycloalkyl groups of 3 to 7 carbons,phenyl, naphthyl, heterocycles, —OR¹⁶ (wherein R¹⁶ represents hydrogen,an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, abenzyl group or a heterocycle), —O—CO—R¹⁶ (wherein R¹⁶ representshydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthylgroup, a benzyl group or a heterocycle), —NR¹⁷R¹⁸ (wherein R¹⁷ and R¹⁸each independently represents hydrogen, an alkyl group of 1 to 4carbons, a heterocycle, an alkylsulfonyl group of 1 to 4 carbons, aphenylsulfonyl group, —SO₂-Het (wherein Het represents a heterocycle),an aminosulfonyl group, a methylaminosulfonyl group, adimethylaminosulfonyl group, a diethylaminosulfonyl group, or an alkylgroup of 1 to 4 carbons substituted with 1 or 2 groups selected fromamong phenyl, heterocycles, phenoxy, —O-Het (wherein Het represents aheterocycle) and hydroxyl, —NH—CO—R¹⁹ (wherein R¹⁹ represents hydrogen,an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, abenzyl group, a heterocycle, an alkoxy group of 1 to 4 carbons or abenzyloxy group), —CO—R²⁰ (wherein R²⁰ represents hydrogen, aheterocycle, an alkoxy group of 1 to 4 carbons, a phenoxy group, abenzyloxy group or —OR²¹ (wherein R²¹ represents hydrogen or aheterocycle)) and —CO—NR²²R²³ (wherein R²² and R²³ each independentlyrepresents hydrogen, an alkyl group of 1 to 4 carbons, a benzyl group ora heterocycle); or R^(4C) which represents an alkyl group of 1 to 4carbons optionally substituted with 1 to 3 groups selected from thegroup consisting of halogens, cycloalkyl groups of 3 to 7 carbons,phenyl, naphthyl, heterocycles, —SH, —OR¹⁶ (wherein R¹⁶ representshydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthylgroup, a benzyl group or a heterocycle), —O—CO—R¹⁶ (wherein R¹⁶represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, anaphthyl group, a benzyl group or a heterocycle), —NR¹⁷R¹⁸ (wherein R¹⁷and R¹⁸ each independently represents hydrogen, an alkyl group of 1 to 4carbons, a heterocycle, an alkylsulfonyl group of 1 to 4 carbons, aphenylsulfonyl group, —SO₂-Het (wherein Het represents a heterocycle),an aminosulfonyl group, a methylaminosulfonyl group, adimethylaminosulfonyl group, a diethylaminosulfonyl group, or an alkylgroup of 1 to 4 carbons substituted with 1 or 2 groups selected fromamong phenyl, heterocycles, phenoxy, —O-Het (wherein Het represents aheterocycle) and hydroxyl, —NH—CO—R¹⁹ (wherein R¹⁹ represents hydrogen,an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, abenzyl group, a heterocycle, an alkoxy group of 1 to 4 carbons or abenzyloxy group), —CO—R²⁰ (wherein R²⁰ represents hydrogen, aheterocycle, an alkoxy group of 1 to 4 carbons, a phenoxy group, abenzyloxy group or —OR²¹ (wherein R²¹ represents hydrogen or aheterocycle)) and —CO—NR²²R²³ (wherein R²² and R²³each independentlyrepresents hydrogen, an alkyl group of 1 to 4 carbons, a benzyl group ora heterocycle); and the numbers in italics represents the positions onthe benzofuran ring; or a salt thereof.
 2. A benzofuryl-α-pyronederivative according to claim 1 wherein R¹ is hydrogen, methyl, ethyl orisopropyl; or a salt thereof.
 3. A benzofuryl-α-pyrone derivativeaccording to claim 1 wherein R¹ is methyl; or a salt thereof.
 4. Abenzofuryl-α-pyrone derivative according to any one of claims 1 to 3,wherein R⁵ is (1) an alkyl group of 1 to 5 carbons optionallysubstituted with 1 to 4 substituents selected from the group consistingof halogens, —OR⁸ (wherein R⁸ represents hydrogen, an alkyl group of 1to 4 carbons, an aryl group of 6 to 10 carbons, an aralkyl group of 7 to20 carbons or a heterocycle), —O—CO—R⁸ (wherein R⁸ represents hydrogen,an alkyl group of 1 to 4 carbons, an aryl group of 6 to 10 carbons, anaralkyl group of 7 to 20 carbons or a heterocycle), —NR⁹R¹⁰ (wherein R⁹and R¹⁰ each independently represents hydrogen, an alkyl group of 1 to 4carbons, an aralkyl group of 7 to 20 carbons, a heterocycle, anoptionally halogen-substituted alkylsulfonyl group of 1 to 4 carbons oran arylsulfonyl group of 6 to 10 carbons), —NH—CO—R²⁴ (wherein R²⁴represents hydrogen, an alkyl group of 1 to 4 carbons, an aryl group of6 to 10 carbons, an aralkyl group of 7 to 20 carbons, a heterocycle, analkoxy group of 1 to 4 carbons or an aralkyloxy group of 7 to 20carbons), cycloalkyl groups of 3 to 7 carbons, aryl groups of 6 to 10carbons, heterocycles and —CO—R²⁵ (wherein R²⁵ represents hydrogen, analkyl group of 1 to 4 carbons, a heterocycle, —OR⁸ (wherein R⁸represents hydrogen, an alkyl group of 1 to 4 carbons, an aryl group of6 to 10 carbons, an aralkyl group of 7 to 20 carbons or a heterocycle)or —NR²⁶R²⁷ (wherein R²⁶ and R²⁷ each independently represents hydrogen,an alkyl group of 1 to 4 carbons, an aralkyl group of 7 to 20 carbons ora heterocycle)), (2) a hydrogen atom, (3) a cycloalkyl group of 3 to 7carbons, (4) an aryl group of 6 to 10 carbons, or (5) a heterocycle; ora salt thereof.
 5. A benzofuryl-α-pyrone derivative according to any oneof claims 1 to 3, wherein R⁵ is (1) an alkyl group of 1 to 5 carbonsoptionally substituted with 1 to 3 substituents selected from the groupconsisting of —OH, alkoxy groups of 1 to 4 carbons, phenoxy, benzyloxy,—O—CO—R²⁸ (wherein R²⁸ represents hydrogen, an alkyl group of 1 to 4carbons, a phenyl group or a heterocycle), —NR²⁹R³⁰ (wherein R²⁹ and R³⁰each independently represents hydrogen, an alkyl group of 1 to 4carbons, a benzyl group, a heterocycle or an optionallyhalogen-substituted alkylsulfonyl group of 1 to 4 carbons), —NH—CO—R³¹(wherein R³¹ represents hydrogen, an alkyl group of 1 to 4 carbons, aheterocycle, an alkoxy group of 1 to 4 carbons or a benzyloxy group),aryl groups of 6 to 10 carbons, heterocycles and —CO—R³² (wherein R³²represents hydrogen, —OR³² (wherein R³² represents hydrogen, an alkylgroup of 1 to 4 carbons, a benzyl group or a heterocycle), —NR³³R³⁴(wherein R³³ and R³⁴ each independently represents hydrogen, methyl,ethyl, benzyl or a heterocycle) or a heterocycle), (2) a cycloalkylgroup of 3 to 7 carbons, (3) an aryl group of 6 to 10 carbons, or (4) aheterocycle; or a salt thereof.
 6. A benzofuryl-α-pyrone derivativeaccording to any one of claims 1 to 3, wherein R⁵ is (1) an alkyl groupof 1 to 5 carbons optionally substituted with 1 to 3 substituentsselected from the group consisting of phenoxy, —NR²⁹R³⁰ (wherein R²⁹ andR³⁰ each independently represents hydrogen, an alkyl group of 1 to 4carbons, a benzyl group, a heterocycle or an optionallyhalogen-substituted alkylsulfonyl group of 1 to 4 carbons), —NH—CO—R³¹(wherein R³¹ represents hydrogen, an alkyl group of 1 to 4 carbons, aheterocycle, an alkoxy group of 1 to 4 carbons or a benzyloxy group),phenyl and —CO—R³⁵ (wherein R³⁵ represents —OH, an alkoxy group of 1 to4 carbons, a benzyloxy group, —NR³³R³⁴ (wherein R³³ and R³⁴ eachindependently represents hydrogen, methyl, ethyl, benzyl or aheterocycle) or a heterocycle), (2) an aryl group of 6 to 10 carbons, or(3) a heterocycle; or a salt thereof.
 7. A benzofuryl-α-pyronederivative according to any one of claims 1 to 3, wherein R⁵ is (1) analkyl group of 1 to 5 carbons optionally substituted with 1 or 2substituents selected from the group consisting of phenoxy, —NR³⁶R³⁷(wherein R³⁶ and R³⁷ each independently represents hydrogen or methyl),—NH—CO—R³⁸ (wherein R³⁸ represents hydrogen, methyl, a heterocycle,t-butoxy or benzyloxy), phenyl and —CO—R³⁹ (wherein R³⁹ represents aheterocycle), (2) a phenyl group, or (3) a heterocycle; or a saltthereof.
 8. A benzofuryl-α-pyrone derivative according to any one ofclaims 1 to 7, wherein R² is hydrogen or —CO—R⁵; or a salt thereof.
 9. Abenzofuryl-α-pyrone derivative according to any one of claims 1 to 3,wherein R² is hydrogen, acetyl, isobutyryl, benzoyl, 4-methoxybenzoyl,2,4-dimethoxybenzoyl, 4-hydroxymethylbenzoyl, 3-dimethylaminobenzoyl,4-acetylaminobenzoyl, phenylacetyl, 3-phenylpropionyl, phenoxyacetyl,furan-2-carbonyl, pyridine-4-carbonyl, pyridine-3-carbonyl,pyridine-2-carbonyl, 6-hydroxypyridine-3-carbonyl, 2-aminoacetyl,2-(t-butoxycarbonylamino)acetyl,2-(N-carbobenzyloxy-N-methylamino)acetyl,1-carbobenzyloxy-2-pyrrolidone-5-carbonyl, 2-pyrrolidone-5-carbonyl,3-acetylamino-4-morpholinyl-4-oxobutyryl, trifluoromethanesulfonyl ormethanesulfonyl; or a salt thereof.
 10. A benzofuryl-α-pyrone derivativeaccording to any one of claims 1 to 3, wherein R² is hydrogen or acetyl;or a salt thereof.
 11. A benzofuryl-α-pyrone derivative according to anyone of claims 1 to 10, wherein R³ is hydrogen, an alkyl group of 1 to 5carbons, an alkenyl group of 2 to 5 carbons, an alkynyl group of 2 to 5carbons, 2-cycloalkylmethyl group of 4 to 8 carbons, a cycloalkylethylgroup of 5 to 9 carbons, a phenyl group, a benzyl group, a phenethylgroup, a methoxy group or a phenoxy group; or a salt thereof.
 12. Abenzofuryl-α-pyrone derivative according to any one of claims 1 to 10,wherein R³ is hydrogen, an alkyl group of 1 to 5 carbons, an alkenylgroup of 2 to 4 carbons, a cycloalkylmethyl group of 6 to 7 carbons,2-cycloalkylethyl group of 7 to 8 carbons, a phenyl group, a benzylgroup, a methoxy group or a phenoxy group; or a salt thereof.
 13. Abenzofuryl-α-pyrone derivative according to any one of claims 1 to 10wherein R³ is an alkyl group of 1 to 5 carbons; or a salt thereof.
 14. Abenzofuryl-α-pyrone derivative according to any one of claims 1 to 10wherein R³ is methyl or ethyl; or a salt thereof.
 15. Abenzofuryl-α-pyrone derivative according to any one of claims 1 to 14,wherein R^(4c) is an alkyl group of 1 to 3 carbons optionallysubstituted with 1 to 3 substituents selected from the group consistingof heterocycles, —SH, —OH, alkoxy groups of 1 to 4 carbons, acyloxygroups of 1 to 4 carbons, —NR⁴OR⁴¹ (wherein R⁴⁰ and R⁴¹ eachindependently represents hydrogen, an alkyl group of 1 to 4 carbons, anoptionally halogen-substituted alkylsulfonyl group of 1 to 4 carbons, oran alkyl group of 1 or 2 carbons substituted with 1 or 2 substituentsselected from among phenyl, heterocycles, phenoxy, —O-Het (wherein Hetrepresents a heterocycle) and hydroxyl), —NH—CO—R⁴² (wherein R⁴²represents hydrogen, phenyl, an alkyl group of 1 to 4 carbons or analkoxy group of 1 to 4 carbons), —CO—R⁴³ (wherein R⁴³ representshydrogen, a heterocycle, an alkoxy group of 1 to 4 carbons or —OR²¹(wherein R²¹ represents hydrogen or a heterocycle)) and —CO—NR⁴⁴R⁴⁵(wherein R⁴⁴ and R⁴⁵ each independently represents hydrogen, an alkylgroup of 1 to 4 carbons or a heterocycle); or a salt thereof.
 16. Abenzofuryl-α-pyrone derivative according to any one of claims 1 to 14,wherein R^(4c) is an alkyl group of 1 to 3 carbons substituted with aheterocycle, —SH, benzoylamino, an acylamino group of 1 to 5 carbons or—NR⁴⁰R⁴¹ (wherein R⁴⁰ and R⁴¹ each independently represents hydrogen, analkyl group of 1 to 4 carbons, an optionally halogen-substitutedalkylsulfonyl group of 1 to 4 carbons, or an alkyl group of 1 or 2carbons substituted with 1 or 2 substituents selected from among phenyl,heterocycles, phenoxy, —O-Het (wherein Het represents a heterocycle) andhydroxyl); or a salt thereof.
 17. A benzofuryl-α-pyrone derivativeaccording to any one of claims 1 to 14, wherein R^(4c) is(3,5-dioxo-2,4-thiazolidinyl)methyl, (3,5-dioxo-2,4-oxazolidinyl)methyl,(2,5-dioxoimidazolidin-4-yl)methyl or(5-oxo-3-thioxo-2,4-thiazolidinyl)methyl; or a salt thereof.
 18. Abenzofuryl-α-pyrone derivative according to any one of claims 1 to 14,wherein R^(4c) is (3,5-dioxo-2,4-thiazolidinyl)methyl; or a saltthereof.
 19. A benzofuryl-α-pyrone derivative according to any one ofclaims 1 to 18, wherein R^(4b) is an alkoxy group of 1 to 6 carbonsoptionally substituted with 1 to 3 substituents selected from the groupconsisting of halogens, cycloalkyl groups of 3 to 7 carbons, phenyl,naphthyl, heterocycles, acyloxy groups of 1 to 4 carbons, —CHO, —CO₂H,alkoxycarbonyl groups of 2 to 5 carbons, —OR⁴⁶ (wherein R⁴⁶ representshydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a benzylgroup or a heterocycle) and —NR⁴⁷R⁴⁸ (wherein R⁴⁷ and R⁴⁸ eachindependently represents hydrogen, an alkyl group of 1 to 4 carbons, analkoxycarbonyl group of 2 to 5 carbons, a heterocycle, an alkylsulfonylgroup of 1 to 4 carbons, a phenylsulfonyl group, —SO₂-Het (wherein Hetrepresents a heterocycle), an aminosulfonyl group, a methylaminosulfonylgroup, a dimethylaminosulfonyl group, a diethylaminosulfonyl group, anacyl group of 1 to 5 carbons, a benzoyl group, —CO-Het (wherein Hetrepresents a heterocycle), a benzyloxycarbonyl group, or an alkyl groupof 1 to 4 carbons substituted with 1 or 2 groups selected from amongphenyl, heterocycles, phenoxy, —O-Het (wherein Het represents aheterocycle) and hydroxyl) or an unsaturated alkoxy group of 3 to 6carbons; or a salt thereof.
 20. A benzofuryl-α-pyrone derivativeaccording to any one of claims 1 to 18, wherein R^(4b) is methoxy,2-propynyloxy, 2,2-dimethylpropoxy, cyclopentylmethoxy, 2-bromoethoxy,benzyloxy, chlorobenzyloxy, fluorobenzyloxy, (trifluoromethyl)benzyloxy,dichlorobenzyloxy, dimethylbenzyloxy, methoxybenzyloxy,sulfamoylbenzyloxy, (methylenedioxy)benzyloxy, carboxybenzyloxy,(methoxycarbonyl)benzyloxy, n-butoxybenzyloxy, aminobenzyloxy,(t-butoxycarbonylamino)benzyloxy, 3-phenylpropoxy,di(methoxyphenyl)methoxy, 1-methyl-1-phenylethoxy, naphthylmethoxy,thienylmethoxy, 2-(morpholinesulfonyl)thienylmethoxy, pyridylmethoxy,(2-methoxypyridyl)methoxy, 2-(pyridyl)ethoxy, pyrazinylmethoxy,pyrimidinylmethoxy, oxazolylmethoxy, 4-phenyloxazolylmethoxy,imidazolylmethoxy, 3-tosyl-5-methylimidazolylmethoxy, thiazolylmethoxy,4-methylthiazolylmethoxy, 2-(morpholinesulfonyl)thiazolylmethoxy,2,4-dichlorothiazolylmethoxy, 2-(5-thiazolyl)ethoxy,2-(4-methyl-5-thiazolyl)ethoxy, (3,5-dioxo-2,4-thiazolidinyl)methoxy,N-methylpiperidylmethoxy, (4-oxachroman-2-yl)methoxy,(3,3-dimethyl-2,4-dioxolanyl)methoxy, methoxymethyl,2-(acetyloxy)ethoxy, bis(dimethylaminomethyl)methoxy,4-(t-butoxycarbonylamino)butoxy, ethoxycarbonylmethoxy,2-(methoxycarbonyl)ethoxy, 5-(ethoxycarbonyl)pentyloxy or2-(benzyloxy)ethoxy; or a salt thereof.
 21. A benzofuryl-α-pyronederivative according to any one of claims 1 to 18, wherein R^(4b) ismethoxy, 2-propynyloxy, benzyloxy, chlorobenzyloxy, fluorobenzyloxy,(trifluoromethyl)benzyloxy, dichlorobenzyloxy, dimethylbenzyloxy,methoxybenzyloxy, sulfamoylbenzyloxy, (methylenedioxy)benzyloxy,carboxybenzyloxy, (methoxycarbonyl)benzyloxy, n-butoxybenzyloxy,aminobenzyloxy, (t-butoxycarbonylamino)benzyloxy, thienylmethoxy,2-(morpholinesulfonyl)thienylmethoxy, pyridylmethoxy,(2-methoxypyridyl)methoxy, 2-(pyridyl)ethoxy, pyrazinylmethoxy,pyrimidinylmethoxy, oxazolylmethoxy, 4-phenyloxazolylmethoxy,imidazolylmethoxy, 3-tosyl-5-methylimidazolylmethoxy, thiazolylmethoxy,4-methylthiazolylmethoxy, 2-(morpholinesulfonyl)thiazolylmethoxy,2,4-dichlorothiazolylmethoxy, 2-(5-thiazolyl)ethoxy,2-(4-methyl-5-thiazolyl)ethoxy, (3,5-dioxo-2,4-thiazolidinyl)methoxy,N-methylpiperidylmethoxy or methoxymethyl; or a salt thereof.
 22. Abenzofuryl-α-pyrone derivative according to any one of claims 1 to 21,wherein R^(4a) is hydrogen, a nitro group, a cyano group, a halogenatom, a heterocycle, A=CH(CH₂)_(n)— (wherein A represents an alicyclicheterocycle, “═” represents a double bond and n represents 0, 1 or 2),A=CH(CH₂)_(m)O— (wherein A represents an alicyclic heterocycle, “═”represents a double bond and m represents 1, 2 or 3), A-SO₂—(CH₂)_(m)—(wherein A represents an alicyclic heterocycle and m represents 1, 2 or3), —OR⁴⁹ (wherein R⁴⁹ represents hydrogen, a heterocycle, an optionallyhalogen-substituted alkylsulfonyl group of 1 to 4 carbons or aphenylsulfonyl group), —O—CO—R⁵⁰ (wherein R⁵⁰ represents hydrogen, analkyl group of 1 to 4 carbons or phenyl), —NR⁵¹R⁵² (wherein R⁵¹ and R⁵²each independently represents hydrogen, an alkyl group of 1 to 4carbons, phenyl, benzyl, —SO₂—R⁵³ (wherein R⁵³ represents phenyl,naphthyl, a heterocycle or an alkyl group of 1 to 3 carbons optionallysubstituted with 1 to 3 substituents selected from the group consistingof halogen atoms, heterocycles and phenyl), or —CO—R⁵⁴ (wherein R⁵⁴represents hydrogen, phenyl, naphthyl, a heterocycle, an alkoxy group of1 to 4 carbons, a phenoxy group, a naphthyloxy group, a heteroaryloxygroup, an aralkyloxy group of 7 to 11 carbons or an alkyl group of 1 to3 carbons optionally substituted with phenyl or a heterocycle)), —CO—R⁵⁵(wherein R⁵⁵ represents hydrogen, —OH, a heterocycle, an alkoxy group of1 to 4 carbons or a phenoxy group), or —CO—NR⁵⁶R⁵⁷ (wherein R⁵⁶ and R⁵⁷each independently represent hydrogen, an alkyl group of 1 to 4 carbons,a cycloalkyl group of 3 to 7 carbons, a phenyl group, a benzyl group, aphenethyl group, a heterocycle or a heterocycle-substituted alkyl groupof 1 to 4 carbons); or a salt thereof.
 23. A benzofuryl-α-pyronederivative according to any one of claims 1 to 21, wherein R^(4a) ishydrogen, a nitro group, a cyano group, a halogen atom, a heterocycle,A=CH(CH₂)_(n)— (wherein A represents an alicyclic heterocycle, “═”represents a double bond and n represents 0, 1 or 2), A=CH(CH₂)_(m)O—(wherein A represents an alicyclic heterocycle, “═” represents a doublebond and m represents 1, 2 or 3), A-SO₂—(CH₂)_(m)— (wherein A representsan alicyclic heterocycle and m represents 1, 2 or 3), —OR⁵⁸ (wherein R⁵⁸represents hydrogen, an optionally halogen-substituted alkylsulfonylgroup of 1 to 4 carbons or a phenylsulfonyl group), —O—CO—R⁵⁹ (whereinR⁵⁹ represents an alkyl group of 1 to 4 carbons or phenyl), —NR⁶⁰R⁶¹(wherein R⁶⁰ and R⁶¹ each independently represents hydrogen, an alkylgroup of 1 to 4 carbons, phenyl, benzyl, —SO₂—R⁶² (wherein R⁶²represents an optionally halogen-substituted alkyl group of 1 to 3carbons, a heterocycle-substituted alkyl group of 1 to 3 carbons, aphenyl group, a heterocycle, a benzyl group or a phenethyl group) or—CO—R⁶³ (wherein R⁶³ represents an alkyl group of 1 to 4 carbons, aphenyl group, an aralkyl group of 7 to 9 carbons, a heterocycle, analkoxy group of 1 to 4 carbons, a heterocycle-substituted alkyl group of1 to 3 carbons, a phenoxy group, a heteroaryloxy group or a benzyloxygroup)), —CO—R⁶⁴ (wherein R⁶⁴ represents hydrogen, —OH or an alkoxygroup of 1 to 4 carbons), or —CO—NR⁶⁵R⁶⁶ (wherein R⁶⁵ and R⁶⁶ eachindependently represents hydrogen, an alkyl group of 1 to 4 carbons, acycloalkyl group of 3 to 7 carbons, a phenyl group, a benzyl group, aphenethyl group, a heterocycle or a heterocycle-substituted alkyl groupof 1 to 4 carbons); or a salt thereof.
 24. A benzofuryl-α-pyronederivative according to any one of claims 1 to 21 wherein R^(4a) ishydrogen, nitro, cyano, bromine, thiazolyl, furyl, thienyl, morpholinyl,piperazinyl, hydroxyl, methanesulfonyloxy, trifluoromethanesulfonyloxy,phenylsulfonyloxy, acetyloxy, benzoyloxy, dimethylamino, dibenzylamino,phenylsulfonylamino, dimethylcarbamoyl, N-methyl-N-phenylcarbamoyl,N-benzyl-N-methylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl,imidazolylcarbamoyl, benzimidazolylcarbamoyl, thiazolylcarbamoyl,benzothiazolylcarbamoyl, isothiazolylcarbamoyl, pyrazolylcarbamoyl,triazolylcarbamoyl, pyridylcarbamoyl, pyrimidinylcarbamoyl,pyrazinylcarbamoyl, isoxazolylcarbamoyl, formyl, carboxyl,methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,t-butoxycarbonyl, acetyl, benzoyl,1,3,4-trihydroisoquinolin-2-ylcarbonyl,(3,5-dioxo-2,4-thiazolidinylidene)methyl,(3,5-dioxo-2,4-oxazolidinylidene)methyl,(2,5-dioxoimidazolidin-4-ylidene)methyl,(5-oxo-3-thioxo-2,4-thiazolidinylidene)methyl,((3,5-dioxo-2,4-thiazolidinyl)sulfonyl)methyl,((3,5-dioxo-2,4-oxazolidinyl)sulfonyl)methyl,((2,5-dioxoimidazolidin-4-yl)sulfonyl)methyl,((5-oxo-3-thioxo-2,4-thiazolidinyl)sulfonyl)methyl or —NR⁶⁷—CO—R⁶⁸(wherein R⁶⁷ represents an alkyl group of 1 to 4 carbons and R⁶⁸represents an alkyl group of 1 to 3 carbons, a phenyl group, aheterocycle, an aralkyl group of 7 to 9 carbons or an alkoxy group of 1to 4 carbons); or a salt thereof.
 25. A benzofuryl-α-pyrone derivativeaccording to any one of claims 1 to 21, wherein R^(4a) is hydrogen,nitro, cyano, bromine, thienyl, piperazinyl, hydroxyl,trifluoromethanesulfonyloxy, phenylsulfonyloxy, acetyloxy,dimethylamino, dibenzylamino, tiazolylcarbamoyl, methoxycarbonyl,isopropoxycarbonyl, (3,5-dioxo-2,4-thiazolidinylidene)methyl, or—N(Me)—CO—R⁶⁹ (wherein R⁶⁹ represents an alkyl group of 1 to 3 carbons,a phenyl group, a heterocycle, a benzyl group or an alkoxy group of 1 to4 carbons); or a salt thereof.
 26. A pharmaceutical compositioncomprising a therapeutically effective dose of a benzofuryl-α-pyronederivative according to any one of claims 1 to 25 or its salt, and apharmaceutically acceptable carrier.
 27. A lipid metabolism enhancercomprising as an active ingredient a benzofuryl-α-pyrone derivativeaccording to any one of claims 1 to 25 or its salt.
 28. A triglyceridebiosynthesis inhibitor comprising as an active ingredient abenzofuryl-α-pyrone derivative according to any one of claims 1 to 25 orits salt.
 29. A blood triglyceride lowering agent comprising as anactive ingredient a benzofuryl-α-pyrone derivative according to any oneof claims 1 to 25 or its salt.
 30. A blood HDL elevating agentcomprising as an active ingredient a benzofuryl-α-pyrone derivativeaccording to any one of claims 1 to 25 or its salt.
 31. Anarteriosclerosis prophylactic agent comprising as an active ingredient abenzofuryl-α-pyrone derivative according to any one of claims 1 to 25 orits salt.
 32. An arteriosclerosis treatment agent comprising as anactive ingredient a benzofuryl-α-pyrone derivative according to any oneof claims 1 to 25 or its salt.